Tricyclic Lactams for Use as Anti-Neoplastic and Anti-Proliferative Agents

ABSTRACT

This invention is in the area of tricyclic lactam compounds and methods for treating selected cancers and hyperproliferative disorders.

RELATED APPLICATIONS

This application claims the benefit of provisional U.S. Application No. 61/980,883, filed Apr. 17, 2014, provisional U.S. Application No. 61/980,895, filed Apr. 17, 2014, provisional U.S. Application No. 61/980,918, filed Apr. 17, 2014, and provisional U.S. Application No. 61/980,939, filed Apr. 17, 2014, which are hereby incorporated by reference for all purposes.

GOVERNMENT INTEREST

The U.S. Government has rights in this invention by virtue of support under Grant No. 5R44AI084284 awarded by the National Institute of Allergy and Infectious Diseases.

FIELD

This invention is in the area of tricyclic lactam compounds and methods for treating selected cancers and hyperproliferative disorders.

BACKGROUND

Cancer is a group of diseases categorized by uncontrolled growth and spread. In the United States in 2013, approximately 1.6 million new cases of cancer were expected to be diagnosed, and over 500,000 people in the U.S. were expected to die from the disease, which is about 1,600 per day (See Cancer Facts and Figures. 2013, American Cancer Society).

All cancers involve a malfunction of genes that control cell growth and division. Although all cancers share that characteristic, cancers vary greatly according to tissue or cell type, which specific genes are down or upregulated, which aspect of the cell cycle is implicated, whether and which cell surface receptors accelerate growth, types of altered metabolism, and which drugs the cancer cells respond to with a therapeutically acceptable effect. Therefore, one of the key goals of cancer research is to identify drugs that show high activity against certain specific target cancers. Non-cancerous cellular hyperproliferation presents a similar problem.

Lymphoid neoplasms are broadly categorized into precursor lymphoid neoplasms and mature T-cell, B-cell or natural killer cell (NK) neoplasms. Chronic leukemias are those likely to exhibit primary manifestations in blood and bone marrow, whereas lymphomas are typically found in extramedullary sites, with secondary events in the blood or bone. Some mature B-cell disorders exhibit dominant immunosecretory manifestations.

Over 79,000 new cases of lymphoma were estimated in 2013. Lymphoma is a cancer of lymphocytes, which are a type of white blood cell. Lymphomas are categorized as Hodgkin or non-Hodgkin. Over 48,000 new cases of leukemias were expected in 2013. They are classified into four main groups according to cell type and rate of growth: acute lymphocytic (ALL), chronic lymphocytic (CLL), acute myeloid (AML), and chronic myeloid (CML).

U.S. Patent Publication 2011/0224227 to Sharpless et al. describes the use of certain CDK4/6 inhibitors, such as PD0332991 and 2BrIC (see Zhu, et al., J. Med. Chem., 46 (11) 2027-2030 (2003); PCT/US2009/059281) to reduce or prevent the effects of cytotoxic compounds on HSPCs in a subject undergoing chemotherapeutic treatments. See also U.S. Patent Publication 2012/0100100.

U.S. Patent Publication 2011/0224221 to Sharpless et al. describes the use of certain CDK4/6 inhibitors, such as PD0332991 and 2BrIC (see Zhu, et al., J. Med. Chem., 46 (11) 2027-2030 (2003); PCT/US2009/059281) to reduce or prevent the deleterious effects of ionizing radiation on HSPCs in a subject exposed to radiation. See also U.S. Patent Publication 2012/0100100.

Stone, et al., Cancer Research 56, 3199-3202 (Jul. 1, 1996) describes reversible, p16-mediated cell cycle arrest as protection from chemotherapy.

WO 2012/061156 filed by Tavares and assigned to G1 Therapeutics describes CDK inhibitors (see also, U.S. Pat. Nos. 8,829,012, 8,822,683, 8,598,186, 8,691,830, and 8,598,197, all assigned to G1 Therapeutics), describe CDK Inhibitors having the basic core structure:

WO 2013/148748 filed by Tavares and assigned to G1 Therapeutics describes Lactam Kinase inhibitors having the basic core structures:

U.S. Patent Publication 2014/0275066 and 2014/0275067, assigned to G1 Therapeutics, describes the use of CDK4/6 inhibitors such as 2′-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′: 1,5]pyrrolo[2,3-d]pyrimidin]-6′-one for the protection of healthy hematopoietic stem and progenitor cells in a subject receiving a DNA-damaging chemotherapeutic agent for the treatment of a Rb-negative tumors.

U.S. Patent Publication 2014/0274896, assigned to G1 Therapeutics, describes the use of CDK4/6 inhibitors such as 2′-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one for the protection of healthy hematopoietic stem and progenitor cells in a subject exposed to ionizing radiation.

U.S. Patent Publication 2014/0271466, assigned to G1 Therapeutics, describes the use of CDK4/6 inhibitors such as 2′-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one for use as an anti-neoplastic for the treatment of a Rb-positive proliferative disorders.

U.S. Patent Publication 2014/0271460, assigned to G1 Therapeutics, describes the use of CDK4/6 inhibitors such as 2′-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one for use an anti-neoplastic for the treatment of a T- or B-cell disorder, for example a leukemia.

WO 2014/144740 assigned to G1 Therapeutics describes pyrrolopyrimidine compounds with CDK4/6 inhibitory activity.

Accordingly, there is an ongoing need for highly active compounds against specific cancers and cellular hyperproliferation.

SUMMARY OF THE INVENTION

The present invention includes the use of an effective amount of a compound described herein, or its pharmaceutically acceptable salt, prodrug, or isotopic variant, optionally in a pharmaceutical composition, to treat a host, typically a human, with a selected cancer, tumor, hyperproliferative condition, or an inflammatory or immune disorder as described further herein. Some of the disclosed compounds are highly active against T-cell proliferation and/or B-cell proliferation and/or NK-cell proliferation.

Disorders include, but are not limited to those involving T-cell proliferation, maintenance of peripheral tolerance, those involving the inappropriate differentiation of Th2 cells, maturation or survival of T and/or B cells, natural killer cell development, or regulation of immunoglobulin class switching in B cells.

In one embodiment, a compound/method of the present invention is used in combination with another therapy to treat the T, B or NK abnormal cellular proliferation, cancer or disorder. The second therapy can be an immunotherapy. For example, the compound can be conjugated to an antibody, radioactive agent or other targeting agent that directs the compound to the diseased or abnormally proliferating cell. In another embodiment, the compound is used in combination with another pharmaceutical or a biologic agent (for example an antibody) to increase the efficacy of treatment with a combined or a synergistic approach. In an embodiment, the compound can be used with T-cell vaccination, which typically involves immunization with inactivated autoreactive T cells to eliminate a pathogenic autoreactive T cell population. In another embodiment, the compound is used in combination with a bispecific T-cell Engager (BiTE), which is an antibody designed to simultaneously bind to specific antigens on endogenous T cells and malignant cells, linking the two types of cells.

In summary, the present invention includes at least the following features:

A) Selective compounds, methods, and compositions for use as chemotherapeutics for the treatment of T-cell cancers and other T-cell mediated disorders; B) Selective compounds, methods, and composition for use as chemotherapeutics for the treatment of B-cell cancers and other B-cell mediated disorders; C) Selective compounds, methods, and compositions for use as immunosuppressants and anti-inflammatory agents; D) Selective compounds, methods and compositions for use against auto-immune disorders; E) The compounds of Formulas I, II, III, IV, V, and VI as described herein, and pharmaceutically acceptable compositions, salts, and prodrugs thereof, for use in medical therapy; F) The compounds of Formulas I, II, III, IV, V, and VI as described herein, and pharmaceutically acceptable compositions, salts, and prodrugs thereof, for use against T-cell cancers and other T-cell mediated disorders; G) The compounds of Formulas I, II, III, IV, V, and VI as described herein, and pharmaceutically acceptable compositions, salts, and prodrugs thereof, for use against B-cell cancers and B-cell mediated disorders; H) The compounds of Formulas I, II, III, IV, V, and VI as described herein, and pharmaceutically acceptable compositions, salts, and prodrugs thereof, for use in the treatment of immune disorders or inflammatory conditions; I) The compounds of Formulas I, II, III, IV, V, and VI as described herein, and pharmaceutically acceptable compositions, salts, and prodrugs thereof, for use in the treatment of autoimmune disorders; J) Processes for the preparation of therapeutic products that contain an effective amount of the compounds of Formulas I, II, III, IV, V, and VI as described herein; K) A method for manufacturing a medicament of Formulas I, II, III, IV, V, and VI intended for therapeutic use; L) Selective compounds, methods, and compositions for use of the compounds of Formulas I, II, III, IV, V, and VI in combination with one or more other therapeutic agents; and M) The compounds of Formulas I, II, III, IV, V, and VI as described herein, and pharmaceutically acceptable compositions, salts, and prodrugs thereof, for use in combination with another one or more additional therapeutic agents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-3 illustrate exemplary embodiments of R² of compounds useful in the described invention.

FIGS. 4A-4C, 5A-5D, 6A-6C, 7A-B, and 8A-8F illustrate exemplary embodiments of the core structure of the compounds useful in the described invention.

DETAILED DESCRIPTION

The present invention includes tricyclic lactam compounds and methods for treatment of certain cancers and hyperproliferative conditions. In particular, compounds and methods are provided to treat cancers and proliferative disorders of hematopoietic cells, and in particular, T cells, B cells, and NK cells. Selected active compounds are also useful to treat inflammatory disorders, auto-immune conditions, and immune disorders.

DEFINITIONS

Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Definition of standard chemistry terms may be found in reference works, including Carey and Sundberg (2007) Advanced Organic Chemistry 5^(th) Ed. Vols. A and B, Springer Science+Business Media LLC, New York. The practice of the present invention will employ, unless otherwise indicated, conventional methods of synthetic organic chemistry, mass spectroscopy, preparative and analytical methods of chromatography, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology. Conventional methods of organic chemistry include those included in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6^(th) Edition, M. B. Smith and J. March, John Wiley & Sons, Inc., Hoboken, N.J., 2007.

The term “alkyl,” either alone or within other terms such as “haloalkyl” and “alkylamino,” embraces linear or branched radicals having one to about twelve carbon atoms. “Lower alkyl” radicals have one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like. The term “alkylene” embraces bridging divalent linear and branched alkyl radicals. Examples include methylene, ethylene, propylene, isopropylene and the like.

The term “alkenyl” embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twelve carbon atoms. “Lower alkenyl” radicals having two to about six carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms “alkenyl” and “lower alkenyl,” embrace radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.

The term “alkynyl” denotes linear or branched radicals having at least one carbon-carbon triple bond and having two to about twelve carbon atoms. “Lower alkynyl” radicals having two to about six carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.

Alkyl, alkenyl, and alkynyl radicals may be optionally substituted with one or more functional groups such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocyclo and the like.

The term “alkylamino” embraces “N-alkylamino” and “N,N-dialkylamino” where amino groups are independently substituted with one alkyl radical and with two alkyl radicals, respectively. “Lower alkylamino” radicals have one or two alkyl radicals of one to six carbon atoms attached to a nitrogen atom. Suitable alkylamino radicals may be mono or dialkylamino such as N-methylamino, N-ethylamino, N.N-dimethylamino, N,N-diethylamino and the like.

The term “halo” means halogens such as fluorine, chlorine, bromine or iodine atoms.

The term “haloalkyl” embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with one or more halo as defined above. Examples include monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals including perhaloalkyl. A monohaloalkyl radical, for one example, may have an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. “Lower haloalkyl” embraces radicals having 1-6 carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. “Perfluoroalkyl” means an alkyl radical having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.

The term “aryl”, alone or in combination, means a carbocyclic aromatic system containing one or two rings wherein such rings may be attached together in a fused manner. The term “aryl” embraces aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. More preferred aryl is phenyl. Said “aryl” group may have 1 or more substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino, and the like. An aryl group may be optionally substituted with one or more functional groups such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocyclo and the like.

The term “heterocyclyl” (or “heterocyclo”) embraces saturated, and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Heterocyclic rings comprise monocyclic 6-8 membered rings, as well as 5-16 membered bicyclic ring systems (which can include bridged fused and spiro-fused bicyclic ring systems). It does not include rings containing —O—O—.—O—S— or —S—S— portions. Said “heterocyclyl” group may have 1 to 3 substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino, lower alkylamino, and the like.

Examples of saturated heterocyclo groups include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl, dihydrothiazolyl, and the like.

Particular examples of partially saturated and saturated heterocyclo groups include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl, and the like.

Heterocyclo groups also includes radicals where heterocyclic radicals are fused/condensed with aryl radicals: unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturated and unsaturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms [e.g. benzofuryl, benzothienyl, 2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl].

The term “heteroaryl” denotes aryl ring systems that contain one or more heteroatoms selected from the group O, N and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized. Examples include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, IH-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The term “heteroarylalkyl” denotes alkyl radicals substituted with a heteroaryl group. Examples include pyridylmethyl and thienylethyl.

The term “sulfonyl”, whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals —SO₂—.

The terms “carboxy” or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes —C(O)—OH.

The term “carbonyl”, whether used alone or with other terms, such as “aminocarbonyl”, denotes —C(O)—.

The term “aminocarbonyl” denotes an amide group of the Formula —C(O)—NH₂.

The terms “heterocycloalkyl” embrace heterocyclic-substituted alkyl radicals. Examples include piperidylmethyl and morpholinylethyl.

The term “arylalkyl” embraces aryl-substituted alkyl radicals. Examples include benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.

The term “cycloalkyl” includes saturated carbocyclic groups of 3 to 10 carbons. Lower cycloalkyl groups include C₃-C₆ rings. Examples include cyclopentyl, cyclopropyl, and cyclohexyl. Cycloalkyl groups may be optionally substituted with one or more functional groups such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocyclo and the like.

The term “cycloalkylalkyl” embraces cycloalkyl-substituted alkyl radicals. “Lower cycloalkylalkyl” radicals are cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Examples of include cyclohexylmethyl. The cycloalkyl in said radicals may be additionally substituted with halo, alkyl, alkoxy and hydroxy.

The term “cycloalkenyl” includes carbocyclic groups having one or more carbon-carbon double bonds including “cycloalkyldienyl” compounds. Examples include cyclopentenyl, cyclopentadienyl, cyclohexenyl and cycloheptadienyl.

The term “comprising” is meant to be open ended, including the indicated component but not excluding other elements.

The term “oxo” as used herein contemplates an oxygen atom attached with a double bond.

The term “nitro” as used herein contemplates —NO₂.

The term “cyano” as used herein contemplates —CN.

As used herein, the term “prodrug” means a compound which when administered to a host in vivo is converted into the parent drug. As used herein, the term “parent drug” means any of the presently described chemical compounds that are useful to treat any of the disorders described herein, or to control or improve the underlying cause or symptoms associated with any physiological or pathological disorder described herein in a host, typically a human. Prodrugs can be used to achieve any desired effect, including to enhance properties of the parent drug or to improve the pharmaceutic or pharmacokinetic properties of the parent. Prodrug strategies exist which provide choices in modulating the conditions for in vivo generation of the parent drug, all of which are deemed included herein. Nonlimiting examples of prodrug strategies include covalent attachment of removable groups, or removable portions of groups, for example, but not limited to acylation, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation or anhydride, among others.

The term “host” refers to an individual, preferably a mammal such as a human. The term “host” can include domesticated animals, such as cats, dogs, etc., livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mouse, monkey, rabbit, rat, guinea pig, etc.) and birds.

Active Compounds

In one embodiment, the invention is directed to compounds or the use of such compounds of Formula I, II, III, IV, or V:

wherein: Z is —(CH₂)_(x)— wherein x is 1, 2, 3 or 4 or —O—(CH₂)_(z)— wherein z is 2, 3 or 4; each X is independently CH or N; each X′ is independently CH or N; X″ is independently CH₂, S or NH, arranged such that the moiety is a stable 5-membered ring; R, R⁸, and R¹¹ are independently H, C₁-C₃ alkyl or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene)_(m)-C₃-C₈ cycloalkyl, -(alkylene)_(m)-aryl, -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valence, and wherein two R^(x) groups bound to the same or adjacent atoms may optionally combine to form a ring; each R¹ is independently aryl, alkyl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally includes O or N heteroatoms in place of a carbon in the chain and two R¹'s on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle; y is 0, 1, 2, 3 or 4; R² is -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-C(O)—O-alkyl; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valence, and wherein two R^(x) groups bound to the same or adjacent atom may optionally combine to form a ring and wherein m is 0, 1 or 2 and n is 0, 1 or 2; R³ and R⁴ at each occurrence are independently:

-   -   (i) hydrogen or     -   (ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl,         cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl         any of which may be optionally independently substituted with         one or more R^(x) groups as allowed by valence, and wherein two         R^(x) groups bound to the same or adjacent atom may optionally         combine to form a ring; or R³ and R⁴ together with the nitrogen         atom to which they are attached may combine to form a         heterocyclo ring optionally independently substituted with one         or more R^(x) groups as allowed by valence, and wherein two         R^(x) groups bound to the same or adjacent atom may optionally         combine to form a ring;         R⁵ and R⁵* at each occurrence is:     -   (i) hydrogen or     -   (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,         heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or         heteroarylalkyl any of which may be optionally independently         substituted with one or more R^(x) groups as allowed by valence;         R^(x) at each occurrence is independently, halo, cyano, nitro,         oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,         cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl,         heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl,         -(alkylene)_(m)-OR⁵, -(alkylene)_(m)-O-alkylene-OR⁵,         -(alkylene)_(m)-S(O)_(n)—R⁵, -(alkylene)_(m)-NR³R⁴,         -(alkylene)_(m)-CN, -(alkylene)_(m)-C(O)—R⁵,         -(alkylene)_(m)-C(S)—R⁵, -(alkylene)_(m)-C(O)—OR⁵,         -(alkylene)_(m)-O—C(O)—R⁵, -(alkylene)_(m)-C(S)—OR⁵,         -(alkylene)_(m)-C(O)-(alkylene)_(m)-NR³R⁴,         -(alkylene)_(m)-C(S)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—NR³R⁴,         -(alkylene)_(m)-N(R³)—C(S)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—R⁵,         -(alkylene)_(m)-N(R³)—C(S)—R⁵, -(alkylene)_(m)-O—C(O)—NR³R⁴,         -(alkylene)_(m)-O—C(S)—NR³R⁴, -(alkylene)_(m)-SO₂—NR³R⁴,         -(alkylene)_(m)-N(R³)—SO₂—R⁵, -(alkylene)_(m)-N(R³)—SO₂—NR³R⁴,         -(alkylene)_(m)-N(R³)—C(O)—OR⁵, -(alkylene)_(m)-N(R³)—C(S)—OR⁵,         or -(alkylene)_(m)-N(R³)—SO₂—R⁵; wherein:     -   said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,         cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl,         heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups         may be further independently substituted with one or more         -(alkylene)_(m)-CN, -(alkylene)_(m)-OR⁵*,         -(alkylene)_(m)-S(O)_(n)—R⁵*, -(alkylene)_(m)-NR³*R⁴*,         -(alkylene)_(m)-C(O)—R⁵*, -(alkylene)_(m)-C(═S)R⁵*,         -(alkylene)_(m)-C(═O)OR⁵*, -(alkylene)_(m)-OC(═O)R⁵*,         -(alkylene)_(m)-C(S)—OR⁵*, -(alkylene)_(m)-C(O)—NR³*R⁴*,         -(alkylene)_(m)-C(S)—NR³*R⁴*,         -(alkylene)_(m)-N(R³*)—C(O)—NR³*R⁴*,         -(alkylene)_(m)-N(R³*)—C(S)—NR³*R⁴*,         -(alkylene)_(m)-N(R³*)—C(O)—R⁵*,         -(alkylene)_(m)-N(R³*)—C(S)—R⁵*, -(alkylene)_(m)-O—C(O)—NR³*R⁴*,         -(alkylene)_(m)-O—C(S)—NR³*R⁴*, -(alkylene)_(m)-SO₂—NR³*R⁴*,         -(alkylene)_(m)-N(R³*)—SO₂—R⁵*,         -(alkylene)_(m)-N(R³*)—SO₂—NR³*R⁴*,         -(alkylene)_(m)-N(R³*)—C(O)—OR⁵*,         -(alkylene)_(m)-N(R³*)—C(S)—OR⁵*, or         -(alkylene)_(m)-N(R³*)—SO₂—R⁵*,     -   n is 0, 1 or 2, and     -   m is 0, 1 or 2;         R³* and R⁴* at each occurrence are independently:     -   (i) hydrogen or     -   (ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl,         heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or         heteroarylalkyl any of which may be optionally independently         substituted with one or more R^(x) groups as allowed by valence;         or R³* and R⁴* together with the nitrogen atom to which they are         attached may combine to form a heterocyclo ring optionally         independently substituted with one or more R^(x) groups as         allowed by valence; and         R⁶ is H or lower alkyl, -(alkylene)m-heterocyclo,         -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴,         -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-O—R⁵,         -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴         any of which may be optionally independently substituted with         one or more R^(x) groups as allowed by valence, and wherein two         R^(x) groups bound to the same or adjacent atoms may optionally         combine to form a ring; and         R¹⁰ is (i) NHR^(A), wherein R^(A) is unsubstituted or         substituted C₁-C₈ alkyl, cycloalkylalkyl, or -TT-RR, C₁-C₈         cycloalkyl or cycloalkyl containing one or more heteroatoms         selected from N, O, and S; TT is an unsubstituted or substituted         C₁-C₈ alkyl or C₃-C₈ cycloalkyl linker; and RR is a hydroxyl,         unsubstituted or substituted C₁-C₆ alkoxy, amino, unsubstituted         or substituted C₁-C₆ alkylamino, unsubstituted or substituted         di-C₁-C₆ alkylamino, unsubstituted or substituted C₆-C₁₀ aryl,         unsubstituted or substituted heteroaryl comprising one or two 5-         or 6-member rings and 1-4 heteroatoms selected from N, O and S,         unsubstituted or substituted C₃-C₁₀ carbocycle, or unsubstituted         or substituted heterocycle comprising one or two 5- or 6-member         rings and 1-4 heteroatoms selected from N, O and S; or (ii)         —C(O)—R¹² or —C(O)O—R¹³, wherein R¹² is NHR^(A) or R^(A) and R¹³         is R^(A);         when compounds comprise a double bond in the 6-membered ring         fused to the pyrimidine ring, two R⁸ groups are present and are         defined above;         when compounds do not comprise a double bond in the 6-membered         ring fused to the pyrimidine ring, four R⁸ groups are present         and are as defined above;         or a pharmaceutically acceptable salt, prodrug or isotopic         variant, for example, partially or fully deuterated form         thereof.

In one embodiment, two R⁸ groups bonded to the same carbon can form an exocyclic double bond. In another embodiment, two R⁸ groups bonded to the same carbon can form a carbonyl group.

In one embodiment, the invention is directed to compounds or the use of such compounds of Formula VI:

wherein R, R¹, R², R³, R⁴, R⁵, R⁶, R^(x), Z, m, n, and y are as defined above; each R¹⁴ is independently H, C₁-C₃ alkyl (including methyl) or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene)_(m)-C₃-C₈ cycloalkyl, -(alkylene)_(m)-aryl, -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valence, and wherein two R^(x) groups bound to the same or adjacent atoms may optionally combine to form a ring; or two R¹⁴ groups bonded to the same carbon can form an exocyclic double bond; or two R¹⁴ groups bonded to the same carbon can form a carbonyl group; and when the compound of Formula VI has a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, two R¹⁴ groups are present as allowed for in Formula VI above; or when the compound of Formula VI does not include a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, four R¹⁴ groups are present as allowed for in Formula VI above; or a pharmaceutically acceptable salt, prodrug or isotopic variant, for example, partially or fully deuterated form thereof.

In an alternative embodiment, the invention is directed to compounds or the use of such compounds of Formula I, II, III, IV, or V:

or a pharmaceutically acceptable salt thereof; wherein: Z is —(CH₂)_(x)— wherein x is 1, 2, 3 or 4 or —O—(CH₂)_(z)— wherein z is 2, 3 or 4; each X is independently CH or N; each X′ is independently CH or N; X″ is independently CH₂, S or NH, arranged such that the moiety is a stable 5-membered ring; R, R⁸, and R¹¹ are independently H, C₁-C₃ alkyl (including methyl) or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene)_(m)-C₃-C₈ cycloalkyl, -(alkylene)_(m)-aryl, -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which, other than heterocyclo, may be optionally independently substituted with one or more R^(x) groups as allowed by valence, and wherein two R^(x) groups bound to the same or adjacent atoms may optionally combine to form a ring; each R¹ is independently aryl, alkyl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally includes O or N heteroatoms in place of a carbon in the chain and two R¹'s on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle; y is 0, 1, 2, 3 or 4; R² is -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-C(O)—O-alkyl; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which, other than heterocyclo, may be optionally independently substituted with one or more R^(x) groups as allowed by valence, and wherein two R^(x) groups bound to the same or adjacent atom may optionally combine to form a ring and wherein m is 0, 1, or 2 and n is 0, 1 or 2; wherein heterocyclo may be optionally independently substituted with 1 to 3 R^(x) groups as allowed by valence, and wherein two R^(x) groups bound to the same or adjacent atom may optionally combine to form a ring; R³ and R⁴ at each occurrence are independently:

-   -   (i) hydrogen or     -   (ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl,         cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl         any of which, other than heterocyclo, may be optionally         independently substituted with one or more R^(x) groups as         allowed by valence, and wherein two R^(x) groups bound to the         same or adjacent atom may optionally combine to form a ring; or         R³ and R⁴ together with the nitrogen atom to which they are         attached may combine to form a heterocyclo ring optionally         independently substituted with one or more R^(x) groups as         allowed by valence, and wherein two R^(x) groups bound to the         same or adjacent atom may optionally combine to form a ring;         R⁵ and R⁵* at each occurrence is:     -   (i) hydrogen or     -   (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,         heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or         heteroarylalkyl any of which, other than heterocyclo, may be         optionally independently substituted with one or more R^(x)         groups as allowed by valence;         R^(x) at each occurrence is independently, halo, cyano, nitro,         oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,         cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl,         heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl,         -(alkylene)_(m)-OR⁵, -(alkylene)_(m)-O-alkylene-OR⁵,         -(alkylene)_(m)-S(O)_(n)—R⁵, -(alkylene)_(m)-NR³R⁴,         -(alkylene)_(m)-CN, -(alkylene)_(m)-C(O)—R⁵,         -(alkylene)_(m)-C(S)—R⁵, -(alkylene)_(m)-C(O)—OR⁵,         -(alkylene)_(m)-O—C(O)—R⁵, -(alkylene)_(m)-C(S)—OR⁵,         -(alkylene)_(m)-C(O)-(alkylene)_(m)-NR³R⁴,         -(alkylene)_(m)-C(S)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—NR³R⁴,         -(alkylene)_(m)-N(R³)—C(S)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—R⁵,         -(alkylene)_(m)-N(R³)—C(S)—R⁵, -(alkylene)_(m)-O—C(O)—NR³R⁴,         -(alkylene)_(m)-O—C(S)—NR³R⁴, -(alkylene)_(m)-SO₂—NR³R⁴,         -(alkylene)_(m)-N(R³)—SO₂—R⁵, -(alkylene)_(m)-N(R³)—SO₂—NR³R⁴,         -(alkylene)_(m)-N(R³)—C(O)—OR⁵, -(alkylene)_(m)-N(R³)—C(S)—OR⁵,         or -(alkylene)_(m)-N(R³)—SO₂—R⁵; wherein:     -   said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,         cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl,         heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups,         any of which, other than heterocyclo, may be further         independently substituted with one or more -(alkylene)_(m)-CN,         -(alkylene)_(m)-OR⁵*, -(alkylene)_(m)-S(O)_(n)—R⁵*,         -(alkylene)_(m)-NR³*R⁴*, -(alkylene)_(m)-C(O)—R⁵*,         -(alkylene)_(m)-C(═S)R⁵*, -(alkylene)_(m)-C(═O)OR⁵*,         -(alkylene)_(m)-OC(═O)R⁵*, -(alkylene)_(m)-C(S)—OR⁵*,         -(alkylene)_(m)-C(O)—NR³*R⁴*, -(alkylene)_(m)-C(S)—NR³*R⁴*,         -(alkylene)_(m)-N(R³*)—C(O)—NR³*R⁴*,         -(alkylene)_(m)-N(R³*)—C(S)—NR³*R⁴*,         -(alkylene)_(m)-N(R³*)—C(O)—R⁵*,         -(alkylene)_(m)-N(R³*)—C(S)—R⁵*, -(alkylene)_(m)-O—C(O)—NR³*R⁴*,         -(alkylene)_(m)-O—C(S)—NR³*R⁴*, -(alkylene)_(m)-SO₂—NR³*R⁴*,         -(alkylene)_(m)-N(R³*)—SO₂—R⁵*,         -(alkylene)_(m)-N(R³*)—SO₂—NR³*R⁴*,         -(alkylene)_(m)-N(R³*)—C(O)—OR⁵*,         -(alkylene)_(m)-N(R³*)—C(S)—OR⁵*, or         -(alkylene)_(m)-N(R³*)—SO₂—R⁵*, and     -   wherein heterocycle may be further independently substituted         with one to three substitutions selected from         -(alkylene)_(m)-CN, -(alkylene)_(m)-OR⁵*,         -(alkylene)_(m)-S(O)_(n)—R⁵*, -(alkylene)_(m)-NR³*R⁴*,         -(alkylene)_(m)-C(O)—R⁵*, -(alkylene)_(m)-C(═S)R⁵*,         -(alkylene)_(m)-C(═O)OR⁵*, -(alkylene)_(m)-OC(═O)R⁵*,         -(alkylene)_(m)-C(S)—OR⁵*, -(alkylene)_(m)-C(O)—NR³*R⁴*,         -(alkylene)_(m)-C(S)—NR³*R⁴*,         -(alkylene)_(m)-N(R³*)—C(O)—NR³*R⁴*,         -(alkylene)_(m)-N(R³*)—C(S)—NR³*R⁴*,         -(alkylene)_(m)-N(R³*)—C(O)—R⁵*,         -(alkylene)_(m)-N(R³*)—C(S)—R⁵*, -(alkylene)_(m)-O—C(O)—NR³*R⁴*,         -(alkylene)_(m)-O—C(S)—NR³*R⁴*, -(alkylene)_(m)-SO₂—NR³*R⁴*,         -(alkylene)_(m)-N(R³*)—SO₂—R⁵*,         -(alkylene)_(m)-N(R³*)—SO₂—NR³*R⁴*,         -(alkylene)_(m)-N(R³*)—C(O)—OR⁵*,         -(alkylene)_(m)-N(R³*)—C(S)—OR⁵*, or         -(alkylene)_(m)-N(R³*)—SO₂—R⁵*;     -   n is 0, 1 or 2, and     -   m is 0, 1; or 2 and         R³* and R⁴* at each occurrence are independently:     -   (i) hydrogen or     -   (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl,         heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or         heteroarylalkyl any of which, other than heterocyclo, may be         optionally independently substituted with one or more R^(x)         groups as allowed by valence; or R³* and R⁴* together with the         nitrogen atom to which they are attached may combine to form a         heterocyclo ring optionally independently substituted with one         or more R^(x) groups as allowed by valence;         R⁶ is H, absent, or lower alkyl, -(alkylene)m-heterocyclo,         -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴,         -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-O—R⁵,         -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴         any of which, other than heterocyclo, may be optionally         independently substituted with one or more R^(x) groups as         allowed by valence, and wherein two R^(x) groups bound to the         same or adjacent atoms may optionally combine to form a ring;         and         R¹⁰ is (i) NHR^(A), wherein R^(A) is unsubstituted or         substituted C₁-C₈ alkyl, cycloalkylalkyl, or -TT-RR, C₁-C₈         cycloalkyl or cycloalkyl containing one or more heteroatoms         selected from N, O, and S; TT is an unsubstituted or substituted         C₁-C₈ alkyl or C₃-C₈ cycloalkyl linker; and RR is a hydroxyl,         unsubstituted or substituted C₁-C₆ alkoxy, amino, unsubstituted         or substituted C₁-C₆ alkylamino, unsubstituted or substituted         di-C₁-C₆ alkylamino, unsubstituted or substituted C₆-C₁₀ aryl,         unsubstituted or substituted heteroaryl comprising one or two 5-         or 6-member rings and 1-4 heteroatoms selected from N, O and S,         unsubstituted or substituted C₃-C₁₀ carbocycle, or unsubstituted         or substituted heterocycle comprising one or two 5- or 6-member         rings and 1-4 heteroatoms selected from N, O and S; or (ii)         —C(O)—R¹² or —C(O)O—R¹³, wherein R¹² is NHR^(A) or R^(A) and R¹³         is R^(A);         when the compound of Formula I, II, III, IV, or V has a double         bond, as indicated by the (----), in the 6-membered ring fused         to the pyrimidine ring, two R⁸ groups are present as allowed for         in Formula I, II, III, IV, or V above; or         when the compound of Formula I, II, III, IV, or V does not         include a double bond, as indicated by the (----), in the         6-membered ring fused to the pyrimidine ring, four R⁸ groups are         present as allowed for in Formula I, II, III, IV, or V above;

-   wherein each heteroaryl is an aryl ring system that contains one or     more heteroatoms selected from the group O, N and S, wherein the     ring nitrogen and sulfur atom(s) are optionally oxidized, and     nitrogen atom(s) are optionally quarternized;

-   wherein each aryl is a carbocyclic aromatic system containing one or     two rings, wherein such rings may be attached together in a fused     manner, and wherein each aryl may have 1 or more R^(x) substituents;

-   wherein each heterocyclo is a saturated or partially saturated     heteroatom-containing ring radical, where the heteroatoms may be     selected from nitrogen, sulfur and oxygen, wherein each heterocyclo     is a monocyclic 6-8 membered ring or a 5-16 membered bicyclic ring     system, and wherein each heterocyclo may have 1 to 3 R^(x)     substituents;     or a pharmaceutically acceptable salt, prodrug or isotopic variant,     for example, partially or fully deuterated form thereof.

In an alternative embodiment, the term “aryl” means a carbocyclic aromatic system containing one or two rings wherein such rings may be attached together in a fused manner, which may have 1 or more substituents selected from lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino.

In an alternative embodiment, the term “heterocyclyl” or “heterocyclo” means a saturated or partially saturated heteroatom-containing ring radical, where the heteroatoms may be selected from nitrogen, sulfur and oxygen, which may have 1 to 3 substituents selected from hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino and lower alkylamino, wherein the heterocyclic ring is a monocyclic 6-8 membered rings, or a 5-16 membered bicyclic ring systems which can include bridged fused and spiro-fused bicyclic ring systems, and which does not include rings containing —O—O—.—O—S— or —S—S— portion.

In an alternative embodiment, the term “heteroaryl” means an aryl ring system that contains one or more heteroatoms selected from the group O, N and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized.

In one embodiment, two R⁸ groups bonded to the same carbon can form an exocyclic double bond. In another embodiment, two R⁸ groups bonded to the same carbon can form a carbonyl group.

In an alternative embodiment, the invention is directed to compounds or the use of such compounds of Formula VI:

wherein R, R¹, R², R³, R⁴, R⁵, R⁶, R^(x), Z, m, n, and y are as defined above; each R¹⁴ is independently H, C₁-C₃ alkyl (including methyl) or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene)_(m)-C₃-C₈ cycloalkyl, -(alkylene)_(m)-aryl, -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which, other than heterocyclo, may be optionally independently substituted with one or more R^(x) groups as allowed by valence, and wherein two R^(x) groups bound to the same or adjacent atoms may optionally combine to form a ring; or two R¹⁴ groups bonded to the same carbon can form an exocyclic double bond; or two R¹⁴ groups bonded to the same carbon can form a carbonyl group; and when the compound of Formula VI has a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, two R¹⁴ groups are present as allowed for in Formula VI above; or when the compound of Formula VI does not include a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, four R¹⁴ groups are present as allowed for in Formula VI above;

-   wherein each heteroaryl is an aryl ring system that contains one or     more heteroatoms selected from the group O, N and S, wherein the     ring nitrogen and sulfur atom(s) are optionally oxidized, and     nitrogen atom(s) are optionally quarternized; -   wherein each aryl is a carbocyclic aromatic system containing one or     two rings, wherein such rings may be attached together in a fused     manner, and wherein each aryl may have 1 or more R^(x) substituents; -   wherein each heterocyclo is a saturated or partially saturated     heteroatom-containing ring radical, where the heteroatoms may be     selected from nitrogen, sulfur and oxygen, wherein each heterocyclo     is a monocyclic 6-8 membered ring or a 5-16 membered bicyclic ring     system, and wherein each heterocyclo may have 1 to 3 R^(x)     substituents;     or a pharmaceutically acceptable salt, prodrug or isotopic variant,     for example, partially or fully deuterated form thereof

In some aspects, the compound is of Formula I or Formula II and R⁶ is absent.

In some aspects, the compound is of Formula III:

and the variables are as defined for compounds of Formulae I and II and pharmaceutically acceptable salts thereof.

In some aspects, R^(x) is not further substituted.

In some aspects, R² is -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valence, and wherein two R^(x) groups bound to the same or adjacent atom may optionally combine to form a ring and wherein m is 0 or 1 and n is 0, 1 or 2.

In some aspects, R⁸ is hydrogen or C₁-C₃ alkyl.

In some aspects, R is hydrogen or C₁-C₃ alkyl.

In some aspects, R² is -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴, -(alkylene)_(m)-C(O)—O-alkyl or -(alkylene)_(m)-OR⁵ any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valence, and wherein two R^(x) groups bound to the same or adjacent atom may optionally combine to form a ring.

In some aspects, R² is -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴, -(alkylene)_(m)-C(O)—O-alkyl or -(alkylene)_(m)-OR⁵ without further substitution.

In some aspects, m in R² is 1. In a further aspect, the alkylene in R² is methylene.

In some aspects, R² is

wherein: R^(2*) is a bond, alkylene, -(alkylene)_(m)-O-(alkylene)_(m)-, -(alkylene)_(m)-C(O)-(alkylene)_(m)-, -(alkylene)_(m)-S(O)₂-(alkylene)_(m)-, or -(alkylene)_(m)-NH-(alkylene)_(m)- wherein each m is independently 0 or 1; P is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group; each R^(x1) is independently -(alkylene)_(m)-(C(O))_(m)-(alkylene)_(m)-(N(R^(N)))_(m)-(alkyl)_(m) wherein each m is independently 0 or 1 provided at least one m is 1, —(C(O))—O-alkyl, -(alkylene)_(m)-cycloalkyl wherein m is 0 or 1, —N(R^(N))-cycloalkyl, —C(O)-cycloalkyl, -(alkylene)_(m)-heterocyclyl wherein m is 0 or 1, or —N(R^(N))-heterocyclyl, —C(O)-heterocyclyl, —S(O)₂-(alkylene)_(m) wherein m is 1 or 2, wherein:

-   -   R^(N) is H, C₁ to C₄ alkyl or C₁ to C₆ heteroalkyl, and     -   wherein two R^(x1) can, together with the atoms to which they         attach on P, which may be the same atom, form a ring; and         t is 0, 1 or 2.

In some aspects, each R^(x1) is only optionally substituted by unsubstituted alkyl, halogen or hydroxy.

In some aspects, R^(x1) is hydrogen or unsubstituted C₁-C₄ alkyl.

In some aspects, at least one R^(x1) is -(alkylene)_(m)-heterocyclyl wherein m is 0 or 1.

In some aspects, R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group.

In some aspects, R² is

In some aspects, R² is

In some aspects, R² is

wherein: R^(2*) is a bond, alkylene, -(alkylene)_(m)-O-(alkylene)_(m)-, -(alkylene)_(m)-C(O)-(alkylene)_(m)-, -(alkylene)_(m)-S(O)₂-(alkylene)_(m)-, or -(alkylene)_(m)-NH-(alkylene)_(m)- wherein each m is independently 0 or 1; P is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group; P1 is a 4- to 6-membered monocyclic saturated heterocyclyl group; each R^(X2) is independently hydrogen or alkyl; and s is 0, 1 or 2.

In some aspects, R² is

In some aspects, P1 includes at least one nitrogen.

In some aspects, any alkylene in R²* in any previous aspect is not further substituted.

In some aspects, R² is selected from the structures depicted in FIGS. 1-3.

In some aspects, R² is

In some aspects, the compound has general Formula I and more specifically one of the general structures in FIGS. 4A-8F wherein the variables are as previously defined.

In some aspects, the compound has general Formula Ia:

wherein R¹, R², R, R⁸, X and y are as previously defined.

In some embodiments, the compound has Formula Ia and R is alkyl.

In some embodiments, the compound has Formula Ia and R is H.

In some embodiments, the compound has Formula Ia and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R^(2*), R^(x1) and t are as previously defined.

In some embodiments, the compound has Formula Ia and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, R^(x1) is hydrogen or unsubstituted C₁-C₄ alkyl and R^(2*) is as previously defined.

In some embodiments, the compound has Formula Ib:

wherein R, R² and R⁸ are as previously defined.

In some embodiments, the compound has Formula Ib and R is alkyl.

In some embodiments, the compound has Formula Ib and R is H.

In some embodiments, the compound has Formula Ib and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R^(2*), R^(x1) and t are as previously defined.

In some embodiments, the compound has Formula Ib and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl and R^(2*) is as previously defined.

In some embodiments, the compound has Formula Ic:

wherein R, R² and R⁸ are as previously defined.

In some embodiments, the compound has Formula Ic and R is alkyl.

In some embodiments, the compound has Formula Ic and R is H.

In some embodiments, the compound has Formula Ic and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R^(2*), R^(x1) and t are as previously defined.

In some embodiments, the compound has Formula Ic and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl and R^(2*) is as previously defined.

In some embodiments, the compound has Formula Id:

wherein R, R² and R⁸ are as previously defined.

In some embodiments, the compound has Formula Id and R is alkyl.

In some embodiments, the compound has Formula Id and R is H.

In some embodiments, the compound has Formula Id and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R^(2*), R^(x1) and t are as previously defined.

In some embodiments, the compound has Formula Id and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl and R^(2*) is as previously defined.

In some embodiments, the compound has Formula Ie:

wherein R, R² and R⁸ are as previously defined.

In some embodiments, the compound has Formula Ie and R is alkyl.

In some embodiments, the compound has Formula Ie and R is H.

In some embodiments, the compound has Formula Ie and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R^(2*), R^(x1) and t are as previously defined.

In some embodiments, the compound has Formula Ie and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl and R^(2*) is as previously defined.

In some embodiments, the compound has Formula If:

wherein R, R² and R⁸ are as previously defined.

In some embodiments, the compound has Formula If and R is alkyl.

In some embodiments, the compound has Formula If and R is H.

In some embodiments, the compound has Formula If and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R^(2*), R^(x1) and t are as previously defined.

In some embodiments, the compound has Formula If and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl and R^(2*) is as previously defined.

In some embodiments, the compound has Formula Ig:

wherein R, R² and R⁸ are as previously defined.

In some embodiments, the compound has Formula Ig and R is alkyl.

In some embodiments, the compound has Formula Ig and R is H.

In some embodiments, the compound has Formula Ig and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R^(2*), R^(x1) and t are as previously defined.

In some embodiments, the compound has Formula Ig and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl and R^(2*) is as previously defined.

In some embodiments, the compound has Formula Ih:

wherein R, R² and R⁸ are as previously defined.

In some embodiments, the compound has Formula Ih and R is alkyl.

In some embodiments, the compound has Formula Ih and R is H.

In some embodiments, the compound has Formula Ih and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R^(2*), R^(x1) and t are as previously defined.

In some embodiments, the compound has Formula Ih and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl and R^(2*) is as previously defined.

In some embodiments, the compound has Formula Ii:

wherein R, R² and R⁸ are as previously defined.

In some embodiments, the compound has Formula Ii and R is alkyl.

In some embodiments, the compound has Formula Ii and R is H.

In some embodiments, the compound has Formula Ii and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R^(2*), R^(x1) and t are as previously defined.

In some embodiments, the compound has Formula Ii and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl and R^(2*) is as previously defined.

In some embodiments, the compound has Formula Ij:

wherein R, R² and R⁸ are as previously defined.

In some embodiments, the compound has Formula Ij and R is alkyl.

In some embodiments, the compound has Formula Ij and R is H.

In some embodiments, the compound has Formula Ij and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group.

In some embodiments, the compound has Formula Ij and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl.

In some embodiments, the compound has the structure:

In some embodiments, the compound has Formula Ij and R is H, and X is CH and N.

In some embodiments, the compound has the structure Ik:

In some embodiments, the compound has Formula Ik and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group.

In some embodiments, the compound has Formula Ik and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl.

In some embodiments, the compound has Formula Il:

In some embodiments, the compound has Formula Il and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group.

In some embodiments, the compound has Formula Il and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl.

In some embodiments, the compound has Formula Im:

In some embodiments, the compound has Formula Im and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group.

In some embodiments, the compound has Formula Im and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl.

In some embodiments, the compound has Formula IIa:

In some embodiments, the compound has Formula IIa and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group.

In some embodiments, the compound has Formula IIa and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl.

In some embodiments, the compound has Formula IIb:

In some embodiments, the compound has Formula IIb and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group.

In some embodiments, the compound has Formula IIb and R² is

wherein P* is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, R^(x1) is hydrogen or C₁-C₄ alkyl.

In some aspects, the active compound is:

Further specific compounds that fall within the present invention and that can be used in the disclosed methods of treatment and compositions include, but are not limited to, the structures listed in Table 1 below.

TABLE 1 Structures of Tricyclic Lactams Structure Reference Structure A

B

C

D

E

F

G

H

I

J

K

L

M

N

O

P

Q

R

S

T

U

V

W

X

Y

Z

AA

BB

CC

DD

EE

FF

GG

HH

II

JJ

KK

LL

MM

NN

OO

PP

QQ

RR

SS

TT

UU

VV

WW

XX

YY

ZZ

AAA

BBB

CCC

DDD

EEE

FFF

GGG

HHH

III

JJJ

KKK

LLL

MMM

NNN

OOO

PPP

QQQ

RRR

SSS

TTT

UUU

VVV

WWW

XXX

YYY

ZZZ

AAAA

BBBB

CCCC

DDDD

EEEE

FFFF

GGGG

HHHH

Isotopic Substitution

The present invention includes compounds and the use of compounds with desired isotopic substitutions of atoms, at amounts above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons. By way of general example and without limitation, isotopes of hydrogen, for example, deuterium (²H) and tritium (³H) may be used anywhere in described structures. Alternatively or in addition, isotopes of carbon, e.g., ¹³C and ¹⁴C, may be used. A preferred isotopic substitution is deuterium for hydrogen at one or more locations on the molecule to improve the performance of the drug. The deuterium can be bound in a location of bond breakage during metabolism (an α-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a β-deuterium kinetic isotope effect).

Substitution with isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Substitution of deuterium for hydrogen at a site of metabolic break down can reduce the rate of or eliminate the metabolism at that bond. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including protium (¹H), deuterium (²H) and tritium (³H). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

The term “isotopically-labeled” analog refers to an analog that is a “deuterated analog”, a “¹³C-labeled analog,” or a “deuterated/¹³C-labeled analog.” The term “deuterated analog” means a compound described herein, whereby a H-isotope, i.e., hydrogen/protium (¹H), is substituted by a H-isotope, i.e., deuterium (²H). Deuterium substitution can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted by at least one deuterium. In certain embodiments, the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In some embodiments it is deuterium that is 90, 95 or 99% enriched at a desired location.

Method of Treatment of Selected Cancer, Tumors, Hyperproliferative Conditions, and Inflammatory and Immune Disorders

In certain aspects, the invention includes the use of an effective amount of a compound described herein, or its pharmaceutically acceptable salt, prodrug or isotopic variant optionally in a pharmaceutical composition, to treat a host, typically a human, with a selected cancer, tumor, hyperproliferative condition or an inflammatory or immune disorder. Some of the disclosed compounds are highly active against T-cell proliferation. Given the paucity of drugs for T-cell cancers and abnormal proliferation, the identification of such uses represents a substantial improvement in the medical therapy for these diseases.

Abnormal proliferation of T-cells, B-cells, and/or NK-cells can result in a wide range of diseases such as cancer, proliferative disorders and inflammatory/immune diseases. A host, for example a human, afflicted with any of these disorders can be treated with an effective amount of a compound as described herein to achieve a decrease in symptoms (a palliative agent) or a decrease in the underlying disease (a disease modifying agent).

Examples include T-cell or NK-cell lymphoma, for example, but not limited to: peripheral T-cell lymphoma; anaplastic large cell lymphoma, for example anaplastic lymphoma kinase (ALK) positive, ALK negative anaplastic large cell lymphoma, or primary cutaneous anaplastic large cell lymphoma; angioimmunoblastic lymphoma; cutaneous T-cell lymphoma, for example mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder; primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma; primary cutaneous gamma-delta T-cell lymphoma; primary cutaneous small/medium CD4+ T-cell lymphoma, and lymphomatoid papulosis; Adult T-cell Leukemia/Lymphoma (ATLL); Blastic NK-cell Lymphoma; Enteropathy-type T-cell lymphoma; Hematosplenic gamma-delta T-cell Lymphoma; Lymphoblastic Lymphoma; Nasal NK/T-cell Lymphomas; Treatment-related T-cell lymphomas; for example lymphomas that appear after solid organ or bone marrow transplantation; T-cell prolymphocytic leukemia; T-cell large granular lymphocytic leukemia; Chronic lymphoproliferative disorder of NK-cells; Aggressive NK cell leukemia; Systemic EBV+ T-cell lymphoproliferative disease of childhood (associated with chronic active EBV infection); Hydroa vacciniforme-like lymphoma; Adult T-cell leukemia/lymphoma; Enteropathy-associated T-cell lymphoma; Hepatosplenic T-cell lymphoma; or Subcutaneous panniculitis-like T-cell lymphoma.

In one embodiment, a compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human, with a lymphoma or lymphocytic or myelocytic proliferation disorder or abnormality. For example, the compounds as described herein can be administered to a host suffering from a Hodgkin Lymphoma or a Non-Hodgkin Lymphoma. For example, the host can be suffering from a Non-Hodgkin Lymphoma such as, but not limited to: an AIDS-Related Lymphoma; Anaplastic Large-Cell Lymphoma; Angioimmunoblastic Lymphoma; Blastic NK-Cell Lymphoma; Burkitt's Lymphoma; Burkitt-like Lymphoma (Small Non-Cleaved Cell Lymphoma); Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; Cutaneous T-Cell Lymphoma; Diffuse Large B-Cell Lymphoma; Enteropathy-Type T-Cell Lymphoma; Follicular Lymphoma; Hepatosplenic Gamma-Delta T-Cell Lymphoma; Lymphoblastic Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Nasal T-Cell Lymphoma; Pediatric Lymphoma; Peripheral T-Cell Lymphomas; Primary Central Nervous System Lymphoma; T-Cell Leukemias; Transformed Lymphomas; Treatment-Related T-Cell Lymphomas; or Waldenstrom's Macroglobulinemia.

Alternatively, a compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human, with a Hodgkin Lymphoma, such as, but not limited to: Nodular Sclerosis Classical Hodgkin's Lymphoma (CHL); Mixed Cellularity CHL; Lymphocyte-depletion CHL; Lymphocyte-rich CHL; Lymphocyte Predominant Hodgkin Lymphoma; or Nodular Lymphocyte Predominant HL.

Alternatively, a compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human with a specific B-cell lymphoma or proliferative disorder such as, but not limited to: multiple myeloma; Diffuse large B cell lymphoma; Follicular lymphoma; Mucosa-Associated Lymphatic Tissue lymphoma (MALT); Small cell lymphocytic lymphoma; Mediastinal large B cell lymphoma; Nodal marginal zone B cell lymphoma (NMZL); Splenic marginal zone lymphoma (SMZL); Intravascular large B-cell lymphoma; Primary effusion lymphoma; or Lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; Hairy cell leukemia; Splenic lymphoma/leukemia, unclassifiable; Splenic diffuse red pulp small B-cell lymphoma; Hairy cell leukemia-variant; Lymphoplasmacytic lymphoma; Heavy chain diseases, for example, Alpha heavy chain disease, Gamma heavy chain disease, Mu heavy chain disease; Plasma cell myeloma; Solitary plasmacytoma of bone; Extraosseous plasmacytoma; Primary cutaneous follicle center lymphoma; T cell/histiocyte rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; Primary mediastinal (thymic) large B-cell lymphoma; Primary cutaneous DLBCL, leg type; ALK+ large B-cell lymphoma; Plasmablastic lymphoma; Large B-cell lymphoma arising in HHV8-associated multicentric; Castleman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma; or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

In one embodiment, a compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human with leukemia. For example, the host may be suffering from an acute or chronic leukemia of a lymphocytic or myelogenous origin, such as, but not limited to: Acute lymphoblastic leukemia (ALL); Acute myelogenous leukemia (AML); Chronic lymphocytic leukemia (CLL); Chronic myelogenous leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (a subtype of AML); large granular lymphocytic leukemia; or Adult T-cell chronic leukemia. In one embodiment, the patient suffers from an acute myelogenous leukemia, for example an undifferentiated AML (MO); myeloblastic leukemia (M1; with/without minimal cell maturation); myeloblastic leukemia (M2; with cell maturation); promyelocytic leukemia (M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]); monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblastic leukemia (M7).

In another embodiment, a compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human with an autoimmune disorder. Examples include, but are not limited to: Acute disseminated encephalomyelitis (ADEM); Addison's disease; Agammaglobulinemia; Alopecia areata; Amyotrophic lateral sclerosis (Also Lou Gehrig's disease; Motor Neuron Disease); Ankylosing Spondylitis; Antiphospholipid syndrome; Antisynthetase syndrome; Atopic allergy; Atopic dermatitis; Autoimmune aplastic anemia; Autoimmune arthritis; Autoimmune cardiomyopathy; Autoimmune enteropathy; Autoimmune granulocytopenia; Autoimmune hemolytic anemia; Autoimmune hepatitis; Autoimmune hypoparathyroidism; Autoimmune inner ear disease; Autoimmune lymphoproliferative syndrome; Autoimmune myocarditis; Autoimmune pancreatitis; Autoimmune peripheral neuropathy; Autoimmune ovarian failure; Autoimmune polyendocrine syndrome; Autoimmune progesterone dermatitis; Autoimmune thrombocytopenic purpura; Autoimmune thyroid disorders; Autoimmune urticarial; Autoimmune uveitis; Autoimmune vasculitis; Balo disease/Balo concentric sclerosis; Behçet's disease; Berger's disease; Bickerstaffs encephalitis; Blau syndrome; Bullous pemphigoid; Cancer; Castleman's disease; Celiac disease; Chagas disease; Chronic inflammatory demyelinating polyneuropathy; Chronic inflammatory demyelinating polyneuropathy; Chronic obstructive pulmonary disease; Chronic recurrent multifocal osteomyelitis; Churg-Strauss syndrome; Cicatricial pemphigoid; Cogan syndrome; Cold agglutinin disease; Complement component 2 deficiency; Contact dermatitis; Cranial arteritis; CREST syndrome; Crohn's disease; Cushing's Syndrome; Cutaneous leukocytoclastic angiitis; Dego's disease; Dercum's disease; Dermatitis herpetiformis; Dermatomyositis; Diabetes mellitus type 1; Diffuse cutaneous systemic sclerosis; Discoid lupus erythematosus; Dressler's syndrome; Drug-induced lupus; Eczema; Endometriosis; Enthesitis-related arthritis; Eosinophilic fasciitis; Eosinophilic gastroenteritis; Eosinophilic pneumonia; Epidermolysis bullosa acquisita; Erythema nodosum; Erythroblastosis fetalis; Essential mixed cryoglobulinemia; Evan's syndrome; Extrinsic and intrinsic reactive airways disease (asthma); Fibrodysplasia ossificans progressive; Fibrosing alveolitis (or Idiopathic pulmonary fibrosis); Gastritis; Gastrointestinal pemphigoid; Glomerulonephritis; Goodpasture's syndrome; Graves' disease; Guillain-Barré syndrome (GBS); Hashimoto's encephalopathy; Hashimoto's thyroiditis; Hemolytic anemia; Henoch-Schonlein purpura; Herpes gestationis (Gestational Pemphigoid); Hidradenitis suppurativa; Hughes-Stovin syndrome; Hypogammaglobulinemia; Idiopathic inflammatory demyelinating diseases; Idiopathic pulmonary fibrosis; Idiopathic thrombocytopenic purpura; IgA nephropathy; Immune glomerulonephritis; Immune nephritis; Immune pneumonitis; Inclusion body myositis; inflammatory bowel disease; Interstitial cystitis; Juvenile idiopathic arthritis aka Juvenile rheumatoid arthritis; Kawasaki's disease; Lambert-Eaton myasthenic syndrome; Leukocytoclastic vasculitis; Lichen planus; Lichen sclerosus; Linear IgA disease (LAD); Lupoid hepatitis aka Autoimmune hepatitis; Lupus erythematosus; Majeed syndrome; microscopic polyangiitis; Miller-Fisher syndrome; mixed connective tissue disease; Morphea; Mucha-Habermann disease aka Pityriasis lichenoides et varioliformis acuta; Multiple sclerosis; Myasthenia gravis; Myositis; Ménière's disease; Narcolepsy; Neuromyelitis optica (also Devic's disease); Neuromyotonia; Occular cicatricial pemphigoid; Opsoclonus myoclonus syndrome; Ord's thyroiditis; Palindromic rheumatism; PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus); Paraneoplastic cerebellar degeneration; Paroxysmal nocturnal hemoglobinuria (PNH); Parry Romberg syndrome; Pars planitis; Parsonage-Turner syndrome; Pemphigus vulgaris; Perivenous encephalomyelitis; Pernicious anaemia; POEMS syndrome; Polyarteritis nodosa; Polymyalgia rheumatic; Polymyositis; Primary biliary cirrhosis; Primary sclerosing cholangitis; Progressive inflammatory neuropathy; Psoriasis; Psoriatic arthritis; pure red cell aplasia; Pyoderma gangrenosum; Rasmussen's encephalitis; Raynaud phenomenon; Reiter's syndrome; relapsing polychondritis; restless leg syndrome; retroperitoneal fibrosis; rheumatic fever; rheumatoid arthritis; Sarcoidosis; Schizophrenia; Schmidt syndrome; Schnitzler syndrome; Scleritis; Scleroderma; Sclerosing cholangitis; serum sickness; Sjögren's syndrome; Spondyloarthropathy; Stiff person syndrome; Still's disease; Subacute bacterial endocarditis (SBE); Susac's syndrome; Sweet's syndrome; Sydenham chorea; sympathetic ophthalmia; systemic lupus erythematosus; Takayasu's arteritis; temporal arteritis (also known as “giant cell arteritis”); thrombocytopenia; Tolosa-Hunt syndrome; transverse myelitis; ulcerative colitis; undifferentiated connective tissue disease; undifferentiated spondyloarthropathy; urticarial vasculitis; vasculitis; vitiligo; viral diseases such as Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicella-Zoster Virus (VZV) and Human Papilloma Virus (HPV); or Wegener's granulomatosis. In some embodiments, the autoimmune disease is an allergic condition, including those from asthma, food allergies, atopic dermatitis, and rhinitis.

In yet another embodiment, a compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human with a disease involving the immune system. In one example, a compound disclosed herein can be used to prevent organ transplant rejection (e.g., allograft rejection and graft versus host disease).

A compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human with a skin disorders such as psoriasis (for example, psoriasis vulgaris), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis). For example, certain substances including some pharmaceuticals when topically applied can cause skin sensitization. In some embodiments, the skin disorder is treated by topical administration of compounds known in the art in combination with the compounds disclosed herein.

A compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human with a proliferative condition such as a myeloproliferative disorder (MPD), polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), and the like.

A compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human with an inflammatory disorder. Example inflammatory diseases include inflammatory diseases of the eye (e.g., iritis, uveitis, conjunctivitis, or related disease), inflammatory diseases of the respiratory tract (e.g., the upper respiratory tract including the nose and sinuses such as rhinitis or sinusitis or the lower respiratory tract including bronchitis, chronic obstructive pulmonary disease, and the like), inflammatory myopathy such as myocarditis, and other inflammatory diseases.

A compound disclosed herein, or its salt, prodrug, or isotopic variant can be used in an effective amount to treat a host, for example a human with an inflammatory ischemic event such as stroke or cardiac arrest.

In another embodiment, the compounds provided herein is useful for the treatment of primary myelofibrosis, post-polycythemia vera myelofibrosis, post-essential thrombocythemia myelofibrosis, and secondary acute myelogenous leukemia. In another embodiment, the compounds provided herein can be used to treat patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. In some embodiments, the host to be treated (e.g., a human) is determined to be non-responsive or resistant to one or more therapies for myeloproliferative disorders. In a particular embodiment, provided herein is a method of treating a myeloproliferative neoplasm in a host in need thereof, comprising administering to the host an effective amount of a composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof.

Combination Therapy

In one aspect of the invention, the compounds disclosed herein can be beneficially administered in combination with another therapeutic regimen for beneficial, additive or synergystic effects.

In one embodiment, a compound/method of the present invention is used in combination with another therapy to treat the T, B or NK abnormal cellular proliferation including cancer or disorder. The second therapy can be an immunotherapy. As discussed in more detail below, the compound can be conjugated to an antibody, radioactive agent or other targeting agent that directs the compound to the diseased or abnormally proliferating cell. In another embodiment, the compound is used in combination with another pharmaceutical or a biologic agent (for example an antibody) to increase the efficacy of treatment with a combined or a synergistic approach. In an embodiment, the compound can be used with T-cell vaccination, which typically involves immunization with inactivated autoreactive T cells to eliminate a pathogenic autoreactive T cell population. In another embodiment, the compound is used in combination with a bispecific T-cell Engager (BiTE), which is an antibody designed to simultaneously bind to specific antigens on endogenous T cells and malignant cells, linking the two types of cells.

In one embodiment, the additional therapy is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Similar to the antibodies produced naturally by B cells, these MAbs “coat” the cancer cell surface, triggering its destruction by the immune system. FDA-approved MAbs of this type include rituximab, which targets the CD20 antigen found on non-Hodgkin lymphoma cells, and alemtuzumab, which targets the CD52 antigen found on B-cell chronic lymphocyticleukemia (CLL) cells. Rituximab may also trigger cell death (apoptosis) directly. Another group of MAbs stimulates an anticancer immune response by binding to receptors on the surface of immune cells and inhibiting signals that prevent immune cells from attacking the body's own tissues, including cancer cells. Other MAbs interfere with the action of proteins that are necessary for tumor growth. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor's microenvironment that promotes the development of tumor blood vessels. When bound to bevacizumab, VEGF cannot interact with its cellular receptor, preventing the signaling that leads to the growth of new blood vessels. Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets the human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from sending their normal growth-promoting signals. They may also trigger apoptosis and activate the immune system to destroy tumor cells. Another group of cancer therapeutic MAbs are the immunoconjugates. These MAbs, which are sometimes called immunotoxins or antibody-drug conjugates, consist of an antibody attached to a cell-killing substance, such as a plant or bacterial toxin, a chemotherapy drug, or a radioactive molecule. The antibody latches onto its specific antigen on the surface of a cancer cell, and the cell-killing substance is taken up by the cell. FDA-approved conjugated MAbs that work this way include ⁹⁰Y-ibritumomab tiuxetan, which targets the CD20 antigen to deliver radioactive yttrium-90 to B-cell non-Hodgkin lymphoma cells; ¹³¹I-tositumomab, which targets the CD20 antigen to deliver radioactive iodine-131 to non-Hodgkin lymphoma cells; and ado-trastuzumab emtansine, which targets the HER-2 molecule to deliver the drug DM1, which inhibits cell proliferation, to HER-2 expressing metastatic breast cancer cells.

Immunotherapies with T cells engineered to recognize cancer cells via bispecific antibodies (bsAbs) or chimeric antigen receptors (CARs) are particularly promising approaches with potential to ablate both dividing and non/slow-dividing subpopulations of cancer cells.

Bispecific antibodies, by simultaneously recognizing target antigen and an activating receptor on the surface of an immune effector cell, offer an opportunity to redirect immune effector cells to kill cancer cells. The other approach is the generation of chimeric antigen receptors by fusing extracellular antibodies to intracellular signaling domains. Chimeric antigen receptor-engineered T cells are able to specifically kill tumor cells in a MHC-independent way.

General anticancer pharmaceutical agents include: Vincristine (Oncovin®) or liposomal vincristine (Marqibo®), Daunorubicin (daunomycin in or Cerubidine®) or doxorubicin (Adriamycin®), Cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L-asparaginase (Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide (VP-16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®), Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, Dexamethasone (Decadron), imatinib (Gleevec®), dasatinib (Spiycel®), nilotinib (Tasigna®), bosutinib (Bosulit®), and ponatinib (Iclusig™), Trastuzumab (Herceptin®), Pertuzumab (Perjeta™), Lapatinib (Tykerb®), Gefitinib (Iressa®), Erlotinib (Tarceva®), Cetuximab (Erbitux®), Panitumumab (Vectibix®), Vandetanib (Caprelsa®), Vemurafenib (Zelboraf®), Vorinostat (Zolinza®), Romidepsin (Istodax®), Bexarotene (Tagretin®), Alitretinoin (Panretin®), Tretinoin (Vesanoid®), Carfilizomib (Kyprolis™), Pralatrexate (Folotyn®), Bevacizumab (Avastin®), Ziv-aflibercept (Zaltrap®), Sorafenib (Nexavar®), Sunitinib (Sutent®), Pazopanib (Votrient®), Regorafenib (Stivarga®), and Cabozantinib (Cometriq™).

Current chemotherapeutic drugs used to treat AML are cytarabine (cytosine arabinoside or ara-C) and the anthracycline drugs (such as daunorubicin/daunomycin, idarubicin, and mitoxantrone). Some of the other chemo drugs that may be used to treat AML include: Cladribine (Leustatin®, 2-CdA), Fludarabine (Fludara®), Topotecan, Etoposide (VP-16), 6-thioguanine (6-TG), Hydroxyurea (Hydrea®), Corticosteroid drugs, such as prednisone or dexamethasone (Decadron®), Methotrexate (MTX), 6-mercaptopurine (6-MP), Azacitidine (Vidaza®), Decitabine (Dacogen®)

Current chemotherapeutic drugs for CLL and other lymphomas include: purine analogs such as fludarabine (Fludara®), pentostatin (Nipent®), and cladribine (2-CdA, Leustatin®), and alkylating agents, which include chlorambucil (Leukeran®) and cyclophosphamide (Cytoxan®) and bendamustine (Treanda®). Other drugs sometimes used for CLL include doxorubicin (Adriamycin®), methotrexate, oxaliplatin, vincristine (Oncovin®), etoposide (VP-16), and cytarabine (ara-C). Other drugs include Rituximab (Rituxan), Obinutuzumab (Gazyva™), Ofatumumab (Arzerra®), Alemtuzumab (Campath®) and Ibrutinib (Imbruvica™).

Current chemotherapies for CML include: Interferon, imatinib (Gleevec), the chemo drug hydroxyurea (Hydrea®), cytarabine (Ara-C), busulfan, cyclophosphamide (Cytoxan®), and vincristine (Oncovin®). Omacetaxine (Synribo®) is a chemo drug that was approved to treat CML that is resistant to some of the TKIs now in use.

CMML is now treated with Deferasirox (Exjade®), cytarabine with idarubicin, cytarabine with topotecan, and cytarabine with fludarabine, Hydroxyurea (hydroxycarbamate, Hydrea®), azacytidine (Vidaza®) and decitabine (Dacogen®).

Erythropoietin (Epo® or Procrit®), a growth factor that promotes red blood cell production, can help avoid transfusions of red blood cells in some patients. Recently it has been found that combining erythropoietin with a growth factor for white blood cells (G-CSF, Neupogen®, or filgrastim) improves the patient's response to the erythropoietin. Darbepoetin (Aranesp®) is a long-acting form of erythropoietin. It works in the same way but can be given less often. Oprelvekin (Neumega®, interleukin-11, or IL-11) can be used to stimulate platelet production after chemotherapy and in some other diseases.

Therapies for multiple myeloma include Pomalidomide (Pomalyst®), Carfilzomib (Kyprolis™), Everolimus (Afinitor®), dexamethasone (Decadron), prednisone and methylprednisolone (Solu-medro®) and hydrocortisone.

Therapies for Hodgkins disease include Brentuximab vedotin (Adcetris™): anti-CD-30, Rituximab, Adriamycin® (doxorubicin), Bleomycin, Vinblastine, Dacarbazine (DTIC).

Monoclonal antibodies for Non-Hodgkins disease include Rituximab (Rituxan®), Ibritumomab (Zevalin®), tositumomab (Bexxar®), Alemtuzumab (Campath®) (CD52 antigen), Ofatumumab (Arzerra®), Brentuximab vedotin (Adcetris®) and Lenalidomide (Revlimid®).

B-cell Lymphoma approved therapies include:

-   -   Diffuse large lymphoma: CHOP (cyclophosphamide, doxorubicin,         vincristine, and prednisone), plus the monoclonal antibody         rituximab (Rituxan). This regimen, known as R-CHOP, is usually         given for about 6 months.     -   Primary mediastinal B-cell lymphoma: R-CHOP.     -   Follicular lymphoma: rituximab (Rituxan) combined with chemo,         using either a single chemo drug (such as bendamustine or         fludarabine) or a combination of drugs, such as the CHOP or CVP         (cyclophosphamide, vincristine, prednisone regimens. The         radioactive monoclonal antibodies, ibritumomab (Zevalin) and         tositumomab (Bexxar) are also possible treatment options. For         patients who may not be able to tolerate more intensive chemo         regimens, rituximab alone, milder chemo drugs (such as         chlorambucil or cyclophosphamide).     -   Chronic lymphocytic leukemia/small lymphocytic lymphoma: R-CHOP.     -   Mantle cell lymphoma: fludarabine, cladribine, or pentostatin;         bortezomib (Velcade) and lenalidomide (Revlimid) and ibrutinib         (Imbruvica).     -   Extranodal marginal zone B-cell lymphoma mucosa-associated         lymphoid tissue (MALT) lymphoma: rituximab; chlorambucil or         fludarabine or combinations such as CVP, often along with         rituximab.     -   Nodal marginal zone B-cell lymphoma: rituximab (Rituxan)         combined with chemo, using either a single chemo drug (such as         bendamustine or fludarabine) or a combination of drugs, such as         the CHOP or CVP (cyclophosphamide, vincristine, prednisone         regimens. The radioactive monoclonal antibodies, ibritumomab         (Zevalin) and tositumomab (Bexxar) are also possible treatment         options. For patients who may not be able to tolerate more         intensive chemo regimens, rituximab alone, milder chemo drugs         (such as chlorambucil or cyclophosphamide).     -   Splenic marginal zone B-cell lymphoma: rituximab; patients with         Hep C-anti-virals.     -   Burkitt lymphoma: methotrexate; hyper-CVAD-cyclophosphamide,         vincristine, doxorubicin (also known as Adriamycin), and         dexamethasone. Course B consists of methotrexate and cytarabine;         CODOX-M-cyclophosphamide, doxorubicin, high-dose         methotrexate/ifosfamide, etoposide, and high-dose cytarabine;         etoposide, vincristine, doxorubicin, cyclophosphamide, and         prednisone (EPOCH) Lymphoplasmacytic lymphoma-rituximab.     -   Hairy cell leukemia-cladribine (2-CdA) or pentostatin;         rituximab; interferon-alfa Current therapies for T-cell         lymphomas include:     -   Precursor T-lymphoblastic lymphoma/leukemia-cyclophosphamide,         doxorubicin (Adriamycin), vincristine, L-asparaginase,         methotrexate, prednisone, and, sometimes, cytarabine (ara-C).         Because of the risk of spread to the brain and spinal cord, a         chemo drug such as methotrexate is also given into the spinal         fluid. Skin lymphomas: Gemcitabine Liposomal doxorubicin         (Doxil); Methotrexate; Chlorambucil; Cyclophosphamide;         Pentostatin; Etoposide; Temozolomide; Pralatrexate; R-CHOP.     -   Angioimmunoblastic lymphoma: prednisone or dexamethasone.     -   Extranodal natural killer/T-cell lymphoma, nasal type: CHOP.     -   Anaplastic large cell lymphoma: CHOP; pralatrexate (Folotyn),         targeted drugs such as bortezomib (Velcade) or romidepsin         (Istodax), or immunotherapy drugs such as alemtuzumab (Campath)         and denileukin diftitox (Ontak).     -   Primary central nervous system (CNS) lymphoma-methotrexate;         rituximab.

A more general list of suitable chemotherapeutic agents include, but are not limited to, radioactive molecules, toxins, also referred to as cytotoxins or cytotoxic agents, which includes any agent that is detrimental to the viability of cells, agents, and liposomes or other vesicles containing chemotherapeutic compounds. Examples of suitable chemotherapeutic agents include but are not limited to 1-dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, alkylating agents, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC)), anti-mitotic agents, cis-dichlorodiamine platinum (II) (DDP) cisplatin), diamino dichloro platinum, anthracyclines, antibiotics, antis, asparaginase, BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucouorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), Chlorambucil, Cisplatin, Cladribine, Colchicin, conjugated estrogens, Cyclophosphamide, Cyclothosphamide, Cytarabine, Cytarabine, cytochalasin B, Cytoxan, Dacarbazine, Dactinomycin, dactinomycin (formerly actinomycin), daunirubicin HCl, daunorucbicin citrate, denileukin diftitox, Dexrazoxane, Dibromomannitol, dihydroxy anthracin dione, Docetaxel, dolasetron mesylate, doxorubicin HCl, dronabinol, E. coli L-asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterified estrogens, estradiol, estramustine phosphate sodium, ethidium bromide, ethinyl estradiol, etidronate, etoposide citrororum factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine HCl, glucocorticoids, goserelin acetate, gramicidin D, granisetron HCl, hydroxyurea, idarubicin HCl, ifosfamide, interferon α-2b, irinotecan HCl, letrozole, leucovorin calcium, leuprolide acetate, levamisole HCl, lidocaine, lomustine, maytansinoid, mechlorethamine HCl, medroxyprogesterone acetate, megestrol acetate, melphalan HCl, mercaptipurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCl, paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCl, plimycin, polifeprosan 20 with carmustine implant, porfimer sodium, procaine, procarbazine HCl, propranolol, rituximab, sargramostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan HCL, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

Additional therapeutic agents that can be administered in combination with the compounds disclosed herein can include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol, finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab, cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, atacicept, rituximab, alemtuzumab, aldesleukine, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, atiprimod, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, belinostat, panobinostat, mapatumumab, lexatumumab, oblimersen, plitidepsin, talmapimod, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, and celecoxib.

In one aspect of the present invention, the compounds disclosed herein are combined with at least one immunosuppressive agent. The immunosuppressive agent may be selected from the group consisting of a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g. Cyclosporin A (NEORAL®), tacrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof, e.g. Sirolimus (RAPAMUNE®), Everolimus (Certican®), temsirolimus, biolimus-7, biolimus-9, a rapalog, e.g. azathioprine, campath 1H, a S1P receptor modulator, e.g. fingolimod or an analogue thereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof, e.g. sodium salt, or a prodrug thereof, e.g. Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®, THYMOGLOBULIN®, Brequinar Sodium, 15-deoxyspergualin, tresperimus, Leflunomide ARAVA®, anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, pimecrolimus (Elidel®), abatacept, belatacept, etanercept (Enbrel®), adalimumab (Humira®), infliximab (Remicade®), an anti-LFA-1 antibody, natalizumab (Antegren®), Enlimomab, ABX-CBL, antithymocyte immunoglobulin, siplizumab, and efalizumab.

In one aspect of the present invention, a compound described herein can be combined with at least one anti-inflammatory agent. The anti-inflammatory agent can be a steroidal anti-inflammatory agent, a nonsteroidal anti-inflammatory agent, or a combination thereof. In some embodiments, anti-inflammatory drugs include, but are not limited to, alclofenac, alclometasone dipropionate, algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen, apazone, balsalazide disodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelains, broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen, clobetasol propionate, clobetasone butyrate, clopirac, cloticasone propionate, cormethasone acetate, cortodoxone, deflazacort, desonide, desoximetasone, dexamethasone dipropionate, diclofenac potassium, diclofenac sodium, diflorasone diacetate, diflumidone sodium, diflunisal, difluprednate, diftalone, dimethyl sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium, epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone, fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin, flunixin meglumine, fluocortin butyl, fluorometholone acetate, fluquazone, flurbiprofen, fluretofen, fluticasone propionate, furaprofen, furobufen, halcinonide, halobetasol propionate, halopredone acetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol, ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole, intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride, lomoxicam, loteprednol etabonate, meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate, mefenamic acid, mesalamine, meseclazone, methylprednisolone suleptanate, morniflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochloride, pentosan polysulfate sodium, phenbutazone sodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone, proxazole, proxazole citrate, rimexolone, romazarit, salcolex, salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin, sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate, tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide, tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium, triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin (acetylsalicylic acid), salicylic acid, corticosteroids, glucocorticoids, tacrolimus, pimecorlimus, prodrugs thereof, co-drugs thereof, and combinations thereof.

In one aspect of the present invention, a compound described herein can be combined with at least one immunomodulatory agent. In one embodiment, the immunomodulatory agent is selected from the group consisting of a CTLA-4 inhibitor, PD-1 or anti-PD-1 agent, IFN-alpha, IFN-beta, and a vaccine, for example, a cancer vaccine. PD-1 inhibitors can include, but are not limited to, nivolumab, CT-011 (pidilizumab), MK-3475 (pembrolizumab), BMS936558, MPDL328OA (Roche), and AMP-514. In one embodiment, the PD-1 agent is Keytruda® (pembrolizumab). In one embodiment, the PD-1 agent is Opdivo (nivolumab). In one embodiment, the CTLA-4 inhibitor is Yervoy® (ipilimumab).

Drugs sometimes used to treat autoimmune disorders include: methylprednisolone oral, Kenalog inj, Medrol oral, Medrol (Pak) oral, Depo-Medrol inj, prednisolone oral, Solu-Medrol inj, Solu-Medrol IV, Cortef oral, hydrocortisone oral, cortisone oral, Celestone Soluspan inj, Orapred oral, Orapred ODT oral, methylprednisolone acetate inj, betamethasone acet & sod phos inj, Veripred 20 oral, Solu-Medrol (PF) inj, methylprednisolone sodium succ IV, Solu-Medrol (PF) IV, methylprednisolone sodium succ inj, Solu-Cortef inj, Pediapred oral, Millipred oral, Aristospan Intra-Articular inj, hydrocortisone sod succinate inj, prednisolone sodium phosphate oral, methylprednisolone sod suc (PF) IV, Flo-Pred oral, triamcinolone hexacetonide inj, A-Hydrocort inj, A-Methapred inj, Millipred DP oral, prednisolone acetate oral, Aristospan Intralesional inj, methylprednisolone sod suc (PF) inj, hydrocortisone sod succ (PF) inj, Solu-Cortef (PF) injection and dexamethasone in 0.9% NaCl IV.

Drug Conjugates

In one embodiment, the activity of an active compound for a purpose described herein can be augmented through conjugation to an agent that targets the diseased or abnormally proliferating cell or otherwise enhances activity, delivery, pharmacokinetics or other beneficial property.

For example, the compound can be administered as an antibody-drug conjugates (ADC). In certain embodiments, a selected compound described herein can be administered in conjugation or combination with an antibody or antibody fragment. Fragments of an antibody can be produced through chemical or genetic mechanisms. In one embodiment, the antibody fragment is an antigen binding fragment. For example, the antigen binding fragment can be selected from an Fab, Fab′, (Fab′)2, or Fv. In one embodiment, the antibody fragment is a Fab. Monovalent F(ab) fragments have one antigen binding site. In one embodiment, the antibody is a divalent (Fab′)2 fragment, which has two antigen binding regions that are linked by disulfide bonds. In one embodiment, the antigen fragment is a (Fab′). Reduction of F(ab′)2 fragments produces two monovalent Fab′ fragments, which have a free sulfhydryl group that is useful for conjugation to other molecules.

In one embodiment, a selected compound described herein can be administered in conjugation or combination with a Fv fragment. Fv fragments are the smallest fragment made from enzymatic cleavage of IgG and IgM class antibodies. Fv fragments have the antigen-binding site made of the VH and VC regions, but they lack the CH1 and CL regions. The VH and VL chains are held together in Fv fragments by non-covalent interactions.

In one embodiment, a selected compound as described herein can be administered in combination with an antibody fragment selected from the group consisting of an ScFv, diabody, triabody, tetrabody, Bis-scFv, minibody, Fab2, or Fab3 antibody fragment. In one embodiment, the antibody fragment is a ScFv. Genetic engineering methods allow the production of single chain variable fragments (ScFv), which are Fv type fragments that include the VH and VL domains linked with a flexible peptide When the linker is at least 12 residues long, the ScFv fragments are primarily monomeric. Manipulation of the orientation of the V-domains and the linker length creates different forms of Fv molecules Linkers that are 3-11 residues long yield scFv molecules that are unable to fold into a functional Fv domain. These molecules can associate with a second scFv molecule, to create a bivalent diabody. In one embodiment, the antibody fragment administered in combination with a selected compound described herein is a bivalent diabody. If the linker length is less than three residues, scFv molecules associate into triabodies or tetrabodies. In one embodiment, the antibody fragment is a triabody. In one embodiment, the antibody fragment is a tetrabody. Multivalent scFvs possess greater functional binding affinity to their target antigens than their monovalent counterparts by having binding to two more target antigens, which reduces the off-rate of the antibody fragment. In one embodiment, the antibody fragment is a minibody. Minibodies are scFv-CH3 fusion proteins that assemble into bivalent dimers. In one embodiment, the antibody fragment is a Bis-scFv fragment. Bis-scFv fragments are bispecific. Miniaturized ScFv fragments can be generated that have two different variable domains, allowing these Bis-scFv molecules to concurrently bind to two different epitopes.

In one embodiment, a selected compound described herein is administered in conjugation or combination with a bispecific dimer (Fab2) or trispecific dimer (Fab3). Genetic methods are also used to create bispecific Fab dimers (Fab2) and trispecific Fab trimers (Fab3). These antibody fragments are able to bind 2 (Fab2) or 3 (Fab3) different antigens at once.

In one embodiment, a selected compound described herein is administered in conjugation or combination with an rIgG antibody fragment. rIgG antibody fragments refers to reduced IgG (75,000 daltons) or half-IgG. It is the product of selectively reducing just the hinge-region disulfide bonds. Although several disulfide bonds occur in IgG, those in the hinge-region are most accessible and easiest to reduce, especially with mild reducing agents like 2-mercaptoethylamine (2-MEA). Half-IgG are frequently prepared for the purpose of targeting the exposing hinge-region sulfhydryl groups that can be targeted for conjugation, either antibody immobilization or enzyme labeling.

In other embodiments, a selected active compound described herein can be linked to a radioisotope to increase efficacy, using methods well known in the art. Any radioisotope that is useful against the T, B or NK abnormal cells can be incorporated into the conjugate, for example, but not limited to ¹³¹I, ¹²³I, ¹⁹²Ir, ³²P, ⁹⁰Sr, ¹⁹⁸Au, ²²⁶Ra, ⁹⁰Y, ²⁴¹Am, ²⁵²Cf, ⁶⁰Co, or ¹³⁷CS.

Of note, the linker chemistry can be important to efficacy and tolerability of the drug conjugates. The thio-ether linked T-DM1 increases the serum stability relative to a disulfide linker version and appears to undergo endosomal degradation, resulting in intra-cellular release of the cytotoxic agent, thereby improving efficacy and tolerability, See, Barginear, M. F. and Budman, D. R., Trastuzumab-DM1: A review of the novel immune-conjugate for HER2-overexpressing breast cancer, The Open Breast Cancer Journal, 1:25-30, 2009.

Examples of early and recent antibody-drug conjugates, discussing drugs, linker chemistries and classes of targets for product development that may be used in the present invention can be found in the reviews by Casi, G. and Neri, D., Antibody-drug conjugates: basic concepts, examples and future perspectives, J. Control Release 161(2):422-428, 2012, Chari, R. V., Targeted cancer therapy: conferring specificity to cytotoxic drugs, Acc. Chem. Rev., 41(1):98-107, 2008, Sapra, P. and Shor, B., Monoclonal antibody-based therapies in cancer: advances and challenges, Pharmacol. Ther., 138(3):452-69, 2013, Schliemann, C. and Neri, D., Antibody-based targeting of the tumor vasculature, Biochim. Biophys. Acta., 1776(2):175-92, 2007, Sun, Y., Yu, F., and Sun, B. W., Antibody-drug conjugates as targeted cancer therapeutics, Yao Xue Xue Bao, 44(9):943-52, 2009, Teicher, B. A., and Chari, R. V., Antibody conjugate therapeutics: challenges and potential, Clin. Cancer Res., 17(20):6389-97, 2011, Firer, M. A., and Gellerman, G. J., Targeted drug delivery for cancer therapy: the other side of antibodies, J. Hematol. Oncol., 5:70, 2012, Vlachakis, D. and Kossida, S., Antibody Drug Conjugate bioinformatics: drug delivery through the letterbox, Comput. Math. Methods Med., 2013; 2013:282398, Epub 2013 Jun. 19, Lambert, J. M., Drug-conjugated antibodies for the treatment of cancer, Br. J. Clin. Pharmacol., 76(2):248-62, 2013, Concalves, A., Tredan, O., Villanueva, C. and Dumontet, C., Antibody-drug conjugates in oncology: from the concept to trastuzumab emtansine (T-DM1), Bull. Cancer, 99(12):1183-1191, 2012, Newland, A. M., Brentuximab vedotin: a CD-30-directed antibody-cytotoxic drug conjugate, Pharmacotherapy, 33(1):93-104, 2013, Lopus, M., Antibody-DM1 conjugates as cancer therapeutics, Cancer Lett., 307(2):113-118, 2011, Chu, Y. W. and Poison, A., Antibody-drug conjugates for the treatment of B-cell non-Hodgkin's lymphoma and leukemia, Future Oncol., 9(3):355-368, 2013, Bertholjotti, I., Antibody-drug conjugate—a new age for personalized cancer treatment, Chimia, 65(9): 746-748, 2011, Vincent, K. J., and Zurini, M., Current strategies in antibody engineering: Fc engineering and pH-dependent antigen binding, bispecific antibodies and antibody drug conjugates, Biotechnol. J., 7(12):1444-1450, 2012, Haeuw, J. F., Caussanel, V., and Beck, A., Immunoconjugates, drug-armed antibodies to fight against cancer, Med. Sci., 25(12):1046-1052, 2009 and Govindan, S. V., and Goldenberg, D. M., Designing immunoconjugates for cancer therapy, Expert Opin. Biol. Ther., 12(7):873-890, 2012.

Pharmaceutical Compositions and Dosage Forms

The active compounds described herein, or their salt, isotopic analog, or prodrug can be administered to the host using any suitable approach which achieves the desired therapeutic result. The amount and timing of active compound administered will, of course, be dependent on the host being treated, the instructions of the supervising medical specialist, on the time course of the exposure, on the manner of administration, on the pharmacokinetic properties of the particular active compound, and on the judgment of the prescribing physician. Thus, because of host to host variability, the dosages given below are a guideline and the physician can titrate doses of the compound to achieve the treatment that the physician considers appropriate for the host. In considering the degree of treatment desired, the physician can balance a variety of factors such as age and weight of the host, presence of preexisting disease, as well as presence of other diseases. Pharmaceutical formulations can be prepared for any desired route of administration including, but not limited to, systemic, topical, oral, intravenous, subcutaneous, transdermal, buccal, sublingual, intraaortal, intranasal, parenteral, or aerosol administration, as discussed in greater detail below.

The therapeutically effective dosage of any active compound described herein will be determined by the health care practitioner depending on the condition, size and age of the patient as well as the route of delivery. In one non-limited embodiment, a dosage from about 0.1 to about 200 mg/kg has therapeutic efficacy, with all weights being calculated based upon the weight of the active compound, including the cases where a salt is employed. In some embodiments, the dosage can be the amount of compound needed to provide a serum concentration of the active compound of up to between about 1 and 5, 10, 20, 30, or 40 μM. In some embodiments, a dosage from about 10 mg/kg to about 50 mg/kg can be employed for oral administration. Typically, a dosage from about 0.5 mg/kg to 5 mg/kg can be employed for intramuscular injection. In some embodiments, dosages can be from about 1 μmol/kg to about 50 μmol/kg, or, optionally, between about 22 μmol/kg and about 33 μmol/kg of the compound for intravenous or oral administration. An oral dosage form can include any appropriate amount of active material, including for example from 5 mg to, 50, 100, 200, or 500 mg per tablet or other solid dosage form.

In accordance with certain embodiments of the invention, in the presently disclosed methods, pharmaceutically active compounds as described herein can be administered orally as a solid or as a liquid, or can be administered intramuscularly, intravenously, or by inhalation as a solution, suspension, or emulsion. In some embodiments, the compounds or salts also can be administered by inhalation, intravenously, or intramuscularly as a liposomal suspension. When administered through inhalation the active compound or salt can be in the form of a plurality of solid particles or droplets having any desired particle size, and for example, from about 0.01, 0.1 or 0.5 to about 5, 10, 20 or more microns, and optionally from about 1 to about 2 microns. Compounds as disclosed in the present invention have demonstrated good pharmacokinetic and pharmacodynamics properties, for instance when administered by the oral or intravenous routes.

The pharmaceutical formulations can comprise an active compound described herein or a pharmaceutically acceptable salt thereof, in any pharmaceutically acceptable carrier. If a solution is desired, water may be the carrier of choice for water-soluble compounds or salts. With respect to the water-soluble compounds or salts, an organic vehicle, such as glycerol, propylene glycol, polyethylene glycol, or mixtures thereof, can be suitable. In the latter instance, the organic vehicle can contain a substantial amount of water. The solution in either instance can then be sterilized in a suitable manner known to those in the art, and for illustration by filtration through a 0.22-micron filter. Subsequent to sterilization, the solution can be dispensed into appropriate receptacles, such as depyrogenated glass vials. The dispensing is optionally done by an aseptic method. Sterilized closures can then be placed on the vials and, if desired, the vial contents can be lyophilized.

In addition to the active compounds or their salts, the pharmaceutical formulations can contain other additives, such as pH-adjusting additives. In particular, useful pH-adjusting agents include acids, such as hydrochloric acid, bases or buffers, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate. Further, the formulations can contain antimicrobial preservatives. Useful antimicrobial preservatives include methylparaben, propylparaben, and benzyl alcohol. An antimicrobial preservative is typically employed when the formulations is placed in a vial designed for multi-dose use. The pharmaceutical formulations described herein can be lyophilized using techniques well known in the art.

For oral administration a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch (e.g., potato or tapioca starch) and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate, and talc are often very useful for tableting purposes. Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules. Materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the compounds of the presently disclosed host matter can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.

In yet another embodiment of the host matter described herein, there are provided injectable, stable, sterile formulations comprising an active compound as described herein, or a salt thereof, in a unit dosage form in a sealed container. The compound or salt is provided in the form of a lyophilizate, which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form liquid formulation suitable for injection thereof into a host. When the compound or salt is substantially water-insoluble, a sufficient amount of emulsifying agent, which is physiologically acceptable, can be employed in sufficient quantity to emulsify the compound or salt in an aqueous carrier. Particularly useful emulsifying agents include phosphatidyl cholines and lecithin.

Additional embodiments provided herein include liposomal formulations of the active compounds disclosed herein. The technology for forming liposomal suspensions is well known in the art. When the compound is an aqueous-soluble salt, using conventional liposome technology, the same can be incorporated into lipid vesicles. In such an instance, due to the water solubility of the active compound, the active compound can be substantially entrained within the hydrophilic center or core of the liposomes. The lipid layer employed can be of any conventional composition and can either contain cholesterol or can be cholesterol-free. When the active compound of interest is water-insoluble, again employing conventional liposome formation technology, the salt can be substantially entrained within the hydrophobic lipid bilayer that forms the structure of the liposome. In either instance, the liposomes that are produced can be reduced in size, as through the use of standard sonication and homogenization techniques. The liposomal formulations comprising the active compounds disclosed herein can be lyophilized to produce a lyophilizate, which can be reconstituted with a pharmaceutically acceptable carrier, such as water, to regenerate a liposomal suspension.

Pharmaceutical formulations also are provided which are suitable for administration as an aerosol by inhalation. These formulations comprise a solution or suspension of a desired compound described herein or a salt thereof, or a plurality of solid particles of the compound or salt. The desired formulations can be placed in a small chamber and nebulized. Nebulization can be accomplished by compressed air or by ultrasonic energy to form a plurality of liquid droplets or solid particles comprising the compounds or salts. The liquid droplets or solid particles may for example have a particle size in the range of about 0.5 to about 10 microns, and optionally from about 0.5 to about 5 microns. The solid particles can be obtained by processing the solid compound or a salt thereof, in any appropriate manner known in the art, such as by micronization. Optionally, the size of the solid particles or droplets can be from about 1 to about 2 microns. In this respect, commercial nebulizers are available to achieve this purpose. The compounds can be administered via an aerosol suspension of respirable particles in a manner set forth in U.S. Pat. No. 5,628,984, the disclosure of which is incorporated herein by reference in its entirety.

When the pharmaceutical formulations suitable for administration as an aerosol is in the form of a liquid, the formulations can comprise a water-soluble active compound in a carrier that comprises water. A surfactant can be present, which lowers the surface tension of the formulations sufficiently to result in the formation of droplets within the desired size range when hosted to nebulization.

The term “pharmaceutically acceptable salts” as used herein refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with hosts (e.g., human hosts) without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the presently disclosed host matter.

Thus, the term “salts” refers to inorganic and organic acid addition salts of compounds of the presently disclosed compounds. These salts can be prepared by any means known in the art, including, without limitation, in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. As the compounds of the presently disclosed host matter are basic compounds, they are all capable of forming a wide variety of different salts with various inorganic and organic acids. Acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms may differ from their respective salt forms in certain physical properties such as solubility in polar solvents. Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as cations, include, but are not limited to, sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include, but are not limited to, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine. The base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms may differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents.

Salts can be prepared from inorganic acids sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, laurylsulphonate and isethionate salts, and the like. Salts can also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and the like. Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts can include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like. See, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference.

Preparation of Active Compounds Syntheses

The disclosed compounds can be made by the following general schemes:

A method for the preparation of substituted tricyclic lactams is provided that includes efficient methods for the preparation of a tricyclic lactam ring system and subsequent displacement of an aryl sulfone with an amine.

In Scheme 1, diethyl succinate is employed to prepare the pyrimidine ester, 2, according to the method of A. Haidle, See, WO 2009/152027 entitled “5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one derivatives for MARK inhibition.” The ester intermediate 2 can be reduced by directly reacting the ester with a reducing agent such as lithium borohydride in a protic organic solvent such as ethanol to produce the corresponding primary alcohol. The primary alcohol can be reacted with a reagent such as phosphorus tribromide in an organic solvent such as dimethylforamide to produce the primary bromide 3. The primary bromide 3 can be condensed with the lactam 4 optionally at low temperature using a base such as lithium diisopropylamide in an organic solvent such as tetrahydrofuran to produce the lactam 5. Lactam 5 can be deprotected by directly reacting Compound 5 with an aqueous acid such as HCl=pH 1 solution. Lactam 6 can be directly reacted with an organic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene in a protic solvent such as ethanol optionally at high temperature to cyclize Compound 5 to form the tricyclic lactam 7. The thiol moiety can be subsequently oxidized to the sulfone 8 by directly reacting Compound 7 with an oxidizing reagent such as meta-chloroperoxybenzoic acid. The sulfone, 8, can be directly reacted with an amine, 9, in the presence of a strong base such as lithium hexamethyldisilazane to form the tricyclic lactam 10.

In Scheme 2, the tricyclic lactam 7 is directly reacted with an oxidizing reagent such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to form the alkene 11. Alkene 11 can be directly reacted with an oxidizing reagent such as meta-chloroperoxybenzoic acid to form the sulfone intermediate 12. The sulfone, 12, can be condensed with an amine, 13, in the presence of a strong base such as lithium hexamethyldisilazane to form the tricyclic lactam 14.

Scheme 3 illustrates the synthesis of a di-protected lactam useful in the preparation of tricyclic lactams. Compound 15 is prepared according to the method of Arigon, J., See, US 2013/0289031 entitled “Pyrimidinone derivatives, preparation thereof and pharmaceutical use thereof” Compound 15 is protected with a suitable protecting group by directly reacting Compound 15 with di-tert-butyl carbonate (Boc anhydride) in the presence of an organic base such as triethylamine or diisopropylethylamine in an organic solvent such as dichloromethane to form the protected amine 16. The protected amine 16 can be directly reacted with methyl chloroacetate in the presence of a base such as potassium carbonate in an organic solvent such as acetonitrile to form the ester 17. The ester 17 can be cyclized by directly reacting the ester with an acid such as hydrochloric acid in a protic solvent such as methanol optionally at a high temperature to form the spirolactam 18. The lactam 18 can be directly reacted with a protecting reagent such as chloromethyl methyl ether (MOM-Cl) in the presence of an organic base such as diisopropylethylamine in an organic solvent such as dichloromethane optionally at a low or at ambient temperature to form the MOM-protected amine 19. The lactam 19 can be protected by directly reacting the lactam with a suitable protecting reagent such as chloromethyl methyl ether (MOM-Cl) in the presence of a base such as sodium bis(trimethylsilyl)amide in an organic solvent such as tetrahydrofuran optionally at a low temperature. Additional lactam intermediates such as Compounds 25 and 31 can be synthesized using analogous chemistry as described for the synthesis of Compound 4. The chemistry for the production of Compounds 25 and 31 is illustrated in Schemes 5 and 6.

Scheme 4 illustrates the coupling of a tricyclic lactam sulfone with an amine to generate compounds of Formula I, II, III, and IV.

Scheme 7 illustrates the preparation of the tricyclic lactam compound 33. Compound 32 is prepared according to the method of Tavares, See, U.S. Pat. No. 8,598,186. Compound 32 is directly reacted with sulfone 8 optionally in the presence of an organic base such as lithium hexamethyldisilazane in the direct presence of amine 32 to form the amine 33. The same chemistry can be employed to produce the alkene compound 34.

In one embodiment a lactam intermediate is treated with BOC-anhydride in the presence of an organic base such as triethylamine in an organic solvent such as dichloromethane. The Boc protected lactam is treated with carbon dioxide in the presence of a nickel catalyst to generate a carboxylic acid. The carboxylic acid is reacted with thionyl chloride in the presence of an organic solvent such as toluene. The resulting acid chloride is treated with an amine to generate an amide that can be deprotected with a strong acid such as trifluoroacetic acid to generate the final target compound.

Alternatively, the lactam can be generated by reacting the carboxylic acid with a protected amine in the presence of a strong acid and a dehydrating agent, which can be together in one moiety as a strong acid anhydride. Examples of strong acid anhydrides include, but are not limited to, trifluoroacetic acid anhydride, tribromoacetic acid anhydride, trichloroacetic acid anhydride, or mixed anhydrides. The dehydrating agent can be a carbodiimide based compound such as but not limited to DCC (N,N-dicyclohexylcarbodiimide), EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or DIC (N,N-diisopropylcarbodiimide). An additional step may be necessary to take off the N-protecting group and the methodologies are known to those skilled in the art Alternatively, the SMe moiety bonded to the pyrimidine ring can be substituted with any leaving group that can be displaced by a primary amine, for example to create an intermediate for a final product such as Br, I, F, SO₂Me, SOalkyl, SO₂alkyl. See, for Example, PCT/US2013/037878 to Tavares.

Other amine intermediates and final amine compounds can be synthesized by those skilled in the art. It will be appreciated that the chemistry can employ reagents that comprise reactive functionalities that can be protected and de-protected and will be known to those skilled in the art at the time of the invention. See for example, Greene, T. W. and Wuts, P. G. M., Greene's Protective Groups in Organic Synthesis, 4^(th) edition, John Wiley and Sons.

[4-Chloro-2-(methylthio)pyrimidin-5-yl]methanol

4-Chloro-2-methylsulfanyl-5-pyrimidinecarboxylate ethyl ester (62 g, 260 mmol) was dissolved in anhydrous tetrahydrofuran (500 mL) in a 3-necked 5 L round bottomed flask fitted with a mechanical stirrer, addition funnel, temperature probe and nitrogen inlet. The solution was cooled to 0° C. Diisobutylaluminum hydride in tetrahydrofuran (1M solution, 800 mL) was added dropwise over a period of 2 hours. After the addition was complete, the reaction mixture was kept at 0° C. for 0.5 hours. The reaction was quenched at 0° C. by the slow addition of saturated aqueous sodium sulfate (265.3 mL, 530.7 mmol) keeping the internal reaction temperature below 10° C. Ethyl acetate (900 mL) was added and the reaction slowly warmed to room temperature overnight. 6M HCl was added till the reaction mixture was slightly acidic (pH 6). The reaction mixture was filtered thru a pad of Celite® and the aluminum salts were washed with ethyl acetate (1 L). The filtrate was poured into a separatory funnel and washed twice with water (600 mL) and finally with brine (600 mL). The organic layer was dried over sodium sulfate, filtered thru Celite® and the solvent concentrated in vacuo to afford 39.2 g (77% crude yield) of a dark yellow oil. The material was used as is for the next step. NMR (CDCl₃) δ 8.56 (s, 1H), 4.76 (s, 2H), 2.59 (s, 3H); MS (ESI+) for C₆H₇ClN₂OS m/z 191.0 (M+H)⁺.

4-Chloro-2-(methylthio)pyrimidine-5-carbaldehyde

[4-Chloro-2-(methylthio)pyrimidin-5-yl]methanol (39.2 g, 206 mmol) was taken up in methylene chloride (520 mL) at room temperature. Manganese (IV) oxide (140 g, 1.60 mol) was added in one portion and the reaction mixture stirred at room temperature overnight. The reaction mixture was filtered through a pad of Celite® and washed with methylene chloride. The filtrate was concentrated under reduced pressure to afford a dark yellow semisolid. The crude product was purified by reverse phase chromatography running a gradient of 1:9 acetonitrile:water (0.1% TFA) to 100% acetonitrile (0.1% TFA). The desired fractions were combined and the acetonitrile was removed under reduced pressure causing precipitation of the desired product. The solids were removed by filtration and the solids washed with water and dried under vacuum at 50° C. Affords 16.6 g (43% yield) of the desired product as a white solid. NMR (CDCl₃) δ 10.32 (s, 1H), 8.88 (s, 1H), 2.65 (s, 3H); MS (ESI+) for C₆H₅ClN₂OS m/z 189.0 (M+H)⁺.

General Procedure A

Ethyl 4-[4-chloro-2-(methylthio)pyrimidin-5-yl]-4-hydroxybut-2-ynoate

Isopropylmagnesium chloride:lithium chloride complex (4.43 g, 30.5 mmol, 25.4 mL of a 1.2M solution) was added to tetrahydrofuran (104 mL) in a 500 mL round bottomed flask which had been flame dried and cooled under Argon. The solution was cooled to −15° C. Ethyl propiolate (3.26 mL, 32.1 mmol) was added dropwise affording a yellow solution. Stirring was continued at −15° C. for 30 minutes and then 4-Chloro-2-(methylthio)pyrimidine-5-carbaldehyde (6.06 g, 32.1 mmol) in tetrahydrofuran (52 mL) was added rapidly. After 10 minutes, the reaction was quenched by the addition of saturated aqueous ammonium chloride (40 mL). The reaction mixture was warmed to room temperature and poured into a separatory funnel partitioning between ethyl acetate (200 mL) and water (100 mL). The organic layer removed and the aqueous layer extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and the solvent removed in vacuo to afford a dark red oil. The product was purified by silica gel chromatography using a gradient of 1:4 to 2:3 ethyl acetate:hexanes which afforded 3.76 g (37% yield) of the desired product as a light red oil. NMR (CDCl₃) δ 8.75 (s, 1H), 5.81 (d, 1H, J=6.0 Hz), 2.72 (bs, 1H), 2.60 (s, 3H), 1.33 (t, 3H, J=7.2 Hz); MS (ESI+) for C₁₁H₁₁ClN₂O₃S m/z 287.9 (M+H)⁺.

tert-Butyl 4-[4-chloro-2-(methylthio)pyrimidin-5-yl]-4-hydroxybut-2-ynoate

Following General Procedure A and using tert-butyl propiolate affords the desired product in 74% yield as a viscous yellow oil. NMR (CDCl₃) δ 8.75 (s, 1H), 5.79 (d, 1H, J=5.4 Hz), 4.27 (q, 2H, J=7.2 Hz), 2.97 (d, 1H, J=5.4 Hz), 2.60 (s, 3H), 1.52 (s, 9H); MS (ESI+) for C₁₃H₁₅ClN₂O₃S m/z 314.9 (M+H)⁺.

General Procedure B

Ethyl 4-[4-chloro-2-(methylthio)pyrimidin-5-yl]-4-oxobut-2-enoate

Ethyl 4-[4-chloro-2-(methylthio)pyrimidin-5-yl]-4-hydroxybut-2-ynoate (3.40 g, 11.8 mmol) was taken up in 1,4-Dioxane (100 mL) at room temperature under argon. Triethylamine (3.3 mL, 24 mmol) was added and the mixture heated to 60° C. for 1 h. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The resultant dark orange oil was re-evaporated twice with toluene. Affords the desired product (3:1 E:Z double bond isomers) in 99% yield as a dark orange oil. NMR (CDCl₃) (major E isomer) δ 8.69 (s, 1H), 7.65 (d, 1H, J=18.0 Hz), 6.81 (d, 1H, J=18.0 Hz), 4.32 (q, 2H, J=6.0 Hz), 2.64 (s, 3H), 1.36 (t, 3H, J=6.0 Hz); NMR (CDCl₃) (minor Z isomer) δ 8.87 (s, 1H), 6.89 (d, 1H, J=12.0 Hz), 6.23 (d, 1H, J=12.0 Hz), 4.14 (q, 2H, J=6.0 Hz), 2.63 (s, 3H), 1.23 (t, 3H, J=6.0 Hz); MS (ESI+) for C₁₁H₁₁ClN₂O₃S m/z 287.0 (M+H)⁺.

tert-Butyl 4-[4-chloro-2-(methylthio)pyrimidin-5-yl]-4-oxobut-2-enoate

Isomerization of tert-butyl 4-[4-chloro-2-(methylthio)pyrimidin-5-yl]-4-hydroxybut-2-ynoate using General Procedure B affords the desired product (5:1 E:Z double bond isomers) in a 99% yield as a viscous dark yellow oil. NMR (CDCl₃) (major E isomer) δ 8.67 (s, 1H), 7.54 (d, 1H, J=15.6 Hz), 6.72 (d, 1H, J=15.6 Hz), 2.64 (s, 3H), 1.54 (s, 9H); NMR (CDCl₃) (minor Z isomer) δ 8.86 (s, 1H), 6.76 (d, 1H, J=12.0 Hz), 6.18 (d, 1H, J=12.0 Hz), 2.63 (s, 3H), 1.40 (s, 9H); MS (ESI+) for C₁₃H₁₅ClN₂O₃S m/z 314.9 (M+H)⁺.

General Procedure C

Ethyl 2-(methylthio)-5-oxo-8-(1-{[(triisopropylsilyl)oxy]methyl}cyclopentyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylate

Ethyl 4-[4-chloro-2-(methylthio)pyrimidin-5-yl]-4-oxobut-2-enoate (3.40 g, 11.8 mmol) was taken up in acetonitrile (20 mL) at room temperature. 1-{[(Triisopropylsilyl)oxy]methyl}cyclopentanamine (3.86 g, 14.2 mmol) was added followed by triethylamine (3.30 mL, 23.7 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was transferred to a separatory funnel transferring with ethyl acetate (250 mL). The organic layer was washed twice with a 10% citric acid (aq) (20 mL)/brine (60 mL) mixture. The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo to afford a yellow oil. The product was purified by silica gel chromatography using a gradient from 1:9 to 2:3 ethyl acetate:hexanes which afforded 2.48 g (41% yield) of the desired product as a pale yellow oil. NMR (CDCl₃) δ 8.58 (s, 1H), 4.72 (m, 1H), 4.46 (m, 1H), 4.16 (q, 2H, J=6.9 Hz), 3.52 (m, 1H), 2.96 (m, 2H), 2.54 (s, 3H), 2.31 (m, 3H), 1.81-1.52 (m, 5H), 1.24 (t, 3H, J=6.9 Hz) 1.08-0.96 (m, 21H); MS (ESI+) for C₂₆H₄₃N₃O₄SSi m/z 522.2 (M+H)⁺.

Ethyl 2-(methylthio)-5-oxo-8-(1-{[(triisopropylsilyl)oxy]methyl}cyclohexyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylate

Cyclization of ethyl 4-[4-chloro-2-(methylthio)pyrimidin-5-yl]-4-oxobut-2-enoate and 1-{[(triisopropylsilyl)oxy]methyl}cyclohexanamine using General Procedure C afforded the desired product in 17% yield as a pale yellow oil. NMR (CDCl₃) δ 8.63 (s, 1H), 4.83 (m, 1H), 4.73 (m, 1H), 4.14 (q, 2H, J=6.0 Hz), 3.86 (m, 1H), 2.97 (m, 2H), 2.55 (s, 3H), 1.97 (m, 1H), 1.72-1.48 (m, 9H), 1.23 (t, 3H, J=6.0 Hz), 1.13-0.95 (m, 21H); MS (ESI+) for C₂₇H₄₅N₃O₄SSi m/z 536.2 (M+H)⁺.

Ethyl 8-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylate

Cyclization of ethyl 4-[4-chloro-2-(methylthio)pyrimidin-5-yl]-4-oxobut-2-enoate and 1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropan-2-amine using General Procedure C afforded the desired product in 52% yield as a pale yellow oil. NMR (CDCl₃) δ 8.62 (s, 1H), 4.94 (m, 1H), 4.18 (m, 3H), 3.63 (m, 1H), 2.93 (m, 2H), 2.57 (s, 3H), 1.71 (s, 3H), 1.55 (s, 3H), 1.23 (t, 3H, J=7.2 Hz), 0.89 (s, 9H), 0.06 (s, 3H), 0.01 (s, 3H); MS (ESI+) for C₂₁H₃₅N₃O₄SSi m/z 454.3 (M+H)⁺.

Ethyl 2-(methylthio)-5-oxo-8-{2-[(triisopropylsilyl)oxy]ethyl}-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylate

Cyclization of ethyl 4-[4-chloro-2-(methylthio)pyrimidin-5-yl]-4-oxobut-2-enoate and 2-[(triisopropylsilyl)oxy]ethanamine using General Procedure C afforded the desired product in 45% yield as a pale yellow oil. NMR (CDCl₃) δ 8.60 (s, 1H), 4.72 (m, 1H), 4.63 (m, 1H), 4.19 (q, 2H, J=6.0 Hz), 3.97 (m, 2H), 3.22 (m, 1H), 3.01 (m, 2H), 2.54 (s, 3H), 1.28 (t, 3H, J=6.0 Hz), 1.17-1.02 (m, 21H); MS (ESI+) for C₂₂H₃₇N₃O₄SSi m/z 468.1 (M+H)⁺.

tert-Butyl 2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylate

Cyclization of tert-Butyl 4-[4-chloro-2-(methylthio)pyrimidin-5-yl]-4-oxobut-2-enoate and 0.5 M ammonia/dioxane using General Procedure C afforded the desired product in 60% yield as an off-white solid. NMR (CDCl₃) δ 8.66 (s, 1H), 6.18 (bs, 1H), 4.34 (m, 1H), 3.05-2.80 (m, 2H), 2.56 (s, 3H), 1.51 (s, 9H); MS (ESI+) for C₁₃H₁₇N₃O₃S m/z 296.0 (M+H)⁺.

General Procedure D

2-(Methylthio)-5-oxo-8-(1-{[(triisopropylsilyl)oxy]methyl}cyclopentyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylic acid

Ethyl 2-(methylthio)-5-oxo-8-(1-{[(triisopropylsilyl)oxy]methyl}cyclopentyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylate (2.48 g, 4.75 mmol) was taken up in tetrahydrofuran (10 mL) and acetonitrile (10 mL) at room temperature. 1M Sodium hydroxide (10 mL, 10 mmol) was added at room temperature for 1 hour. The reaction was quenched by the addition of 10% citric acid till pH ca 6-7. The reaction mixture was transferred to a separatory funnel with water (30 mL) and ethyl acetate (150 mL). The aqueous layer was removed and the organic layer washed with brine (50 mL). The organic layer was dried over sodium sulfate, filtered and the solvent concentrated in vacuo to afford the 2.08 g (89% yield) of the desired product as a dark yellow oil. NMR (CDCl₃) δ 8.46 (s, 1H), 4.58 (m, 1H), 4.39 (m, 1H), 3.71 (m, 1H), 2.88 (m, 2H), 2.51 (s, 3H), 2.26 (m, 3H), 1.97-1.45 (m, 6H) 1.12-0.92 (m, 21H); MS (ESI+) for C₂₄H₃₉N₃O₄SSi m/z 494.2 (M+H)⁺.

2-(Methylthio)-5-oxo-8-(1-{[(triisopropylsilyl)oxy]methyl}cyclohexyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylic acid

Saponification of ethyl 2-(methylthio)-5-oxo-8-(1-{[(triisopropylsilyl)oxy]methyl}cyclohexyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylate using General Procedure D affords the desired product in 95% yield as a dark yellow oil. NMR (CDCl₃) δ 8.58 (s, 1H), 4.75 (m, 1H), 4.53 (m, 1H), 3.96 (m, 1H), 2.99 (m, 2H), 2.54 (s, 3H), 1.93-1.48 (m, 10H), 1.13-0.95 (m, 21H); MS (ESI+) for C₂₅H₄₁N₃O₄SSi m/z 508.1 (M+H)⁺.

8-(2-{[tert-Butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylic acid

Saponification of ethyl 8-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylate using General Procedure D affords the desired product in 99% yield as a pale yellow foam. NMR (CDCl₃) δ 8.69 (s, 1H), 4.88 (m, 1H), 4.51 (m, 1H), 3.82 (m, 1H), 3.17 (m, 1H), 2.79 (m, 1H), 2.57 (s, 3H), 1.65 (s, 3H), 1.60 (s, 3H), 0.92 (s, 9H), 0.11 (s, 6H); MS (ESI+) for C₁₉H₃₁N₃O₄SSi m/z 426.3 (M+H)⁺.

2-(Methylthio)-5-oxo-8-{2-[(triisopropylsilyl)oxy]ethyl}-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylic acid

Saponification of ethyl 2-(methylthio)-5-oxo-8-{2-[(triisopropylsilyl)oxy]ethyl}-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylate using General Procedure D affords the desired product in 98% yield as an orange foam. NMR (CDCl₃) δ 8.56 (s, 1H), 4.71 (m, 1H), 4.54 (m, 1H), 3.99 (m, 2H), 3.32 (m, 1H), 3.01 (m, 2H), 2.53 (s, 3H), 1.16-0.98 (m, 21H); MS (ESI+) for C₂₀H₃₃N₃O₄SSi m/z 440.2 (M+H)⁺.

2-(Methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylic acid

tert-Butyl 2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylate (220 mg, 0.74 mmol) was taken up in trifluoroacetic acid (5 mL) at room temperature under argon. The mixture was stirred at room temperature for 45 minutes. The solvent was removed in vacuo to a pink oil which was re-evaporated first from toluene and finally methanol affording 180 mg (99% yield) of the desired product as an off-white solid. NMR (MeOH-d₄) δ 8.49 (s, 1H), 4.59 (m, 1H), 3.16-2.91 (m, 2H), 2.63 (s, 3H); MS (ESI+) for C₉H₉N₃O₃S m/z 240.0 (M+H)⁺.

General Procedure E

N-(2,4-Dimethoxybenzyl)-2-(methylthio)-5-oxo-8-(1-{[(triisopropylsilyl)oxy]methyl}cyclopentyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxamide

2-(Methylthio)-5-oxo-8-(1-{[(triisopropylsilyl)oxy]methyl}cyclopentyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylic acid (2.08 g, 4.21 mmol) was taken up in N,N-dimethylformamide (30 mL) at room temperature. 1-(2,4-dimethoxyphenyl)methanamine (1.26 mL, 8.42 mmol) was added followed by the addition of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (4.80 g, 12.6 mmol) and N,N-diisopropylethylamine (4.40 mL, 25.3 mmol). The reaction mixture was stirred overnight at room temperature. The product was diluted with water (50 mL) and poured into a separatory funnel. The mixture was extracted with twice with ethyl acetate (150 mL) and the combined organic layers were thrice washed with half-saturated aqueous LiCl (20 mL). The combined organic layers were dried over sodium sulfate, filtered and the solvent removed in vacuo to afford a dark yellow oil. The product was purified by silica gel chromatography using a gradient from 1:4 to 2:3 ethyl acetate:hexanes which afforded 2.39 g (88% yield) of the desired product as a brown sticky solid. NMR (CDCl₃) δ 8.58 (s, 1H), 7.07 (m, 1H), 6.62 (m, 1H), 6.39 (m, 2H), 4.56 (m, 1H), 4.38 (m, 2H), 4.20 (m, 1H), 3.80 (s, 3H), 3.66 (s, 3H), 3.48 (m, 1H), 3.02 (m, 2H), 2.55 (s, 3H), 2.35 (m, 2H), 2.06 (m, 1H), 1.70-1.31 (m, 5H), 1.09-0.90 (m, 21H); MS (ESI+) for C₃₃H₅₀N₄O₅SSi m/z 643.2 (M+H)⁺.

N-(2,4-Dimethoxybenzyl)-2-(methylthio)-5-oxo-8-(1-{[(triisopropylsilyl)oxy]methyl}cyclohexyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxamide

Coupling reaction of 2-(methylthio)-5-oxo-8-(1-{[(triisopropylsilyl)oxy]methyl}cyclohexyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylic acid using General Procedure E afforded the desired product in 52% yield as a yellow solid. NMR (CDCl₃) δ 8.60 (s, 1H), 6.87 (m, 2H), 6.37 (m, 2H), 4.71 (m, 1H), 4.49-4.14 (m, 4H), 3.79 (s, 3H), 3.70 (s, 3H), 3.18 (m, 1H), 2.86 (m, 1H), 2.65 (m, 1H), 2.54 (s, 3H), 2.20 (m, 1H), 1.98 (m, 2H), 1.61-1.48 (m, 6H), 1.08-0.92 (bs, 21H); MS (ESI+) for C₃₄H₅₂N₄O₅SSi m/z 657.2 (M+H)⁺.

8-(2-{[tert-Butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-N-(2,4-dimethoxybenzyl)-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxamide

Coupling reaction of 8-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylic acid using General Procedure E afforded the desired product in 86% yield as a viscous yellow oil. NMR (CDCl₃) δ 8.58 (s, 1H), 6.95 (m, 1H), 6.80 (m, 1H), 6.37 (m, 2H), 4.71 (m, 1H), 4.27 (m, 2H), 4.13 (m, 1H), 3.84 (m, 1H), 3.79 (s, 3H), 3.70 (s, 3H), 3.15 (m, 1H), 2.77 (m, 1H), 2.56 (s, 3H), 1.64 (s, 3H), 1.58 (s, 3H), 0.85 (s, 9H), 0.02 (s, 3H), −0.03 (s, 3H); MS (ESI+) for C₂₈H₄₂N₄O₅SSi m/z 575.4 (M+H)⁺.

N-(2,4-Dimethoxybenzyl)-2-(methylthio)-5-oxo-8-{2-[(triisopropylsilyl)oxy]ethyl}-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxamide

Coupling reaction of 2-(methylthio)-5-oxo-8-{2-[(triisopropylsilyl)oxy]ethyl}-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylic acid using General Procedure E afforded the desired product in 57% yield as a dark yellow solid. NMR (CDCl₃) δ 8.59 (s, 1H), 7.06 (m, 1H), 6.39 (m, 3H), 4.51 (m, 2H), 4.32 (m, 2H), 3.93 (m, 2H), 3.81 (s, 3H), 3.73 (s, 3H), 3.18 (m, 1H), 3.01 (m, 2H), 2.54 (s, 3H), 1.11-0.95 (m, 21H); MS (ESI+) for C₂₉H₄₄N₄O₅SSi m/z 589.4 (M+H)⁺.

2-(Methylthio)-5-oxo-N-(1-{[(triisopropylsilyl)oxy]methyl}cyclopentyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxamide

Coupling reaction of 2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylic acid using General Procedure E afforded the desired product in 94% yield as a dark yellow oil. NMR (CDCl3) δ 8.64 (s, 1H), 6.09 (bs, 1H), 6.04 (bs, 1H), 4.25 (m, 1H), 3.68 (m, 2H), 2.86 (m, 2H), 2.54 (s, 3H), 2.07-1.54 (m, 8H), 1.33-0.96 (m, 21H); MS (ESI+) for C₂₄H₄₀N₄O₃SSi m/z 493.1 (M+H)⁺.

General Procedure F

N-(2,4-Dimethoxybenzyl)-8-[1-(hydroxymethyl)cyclopentyl]-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxamide

N-(2,4-Dimethoxybenzyl)-2-(methylthio)-5-oxo-8-(1-{[(triisopropylsilyl)oxy]methyl}cyclopentyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxamide (2.39 g, 3.72 mmol) was taken up in tetrahydrofuran (42 mL) at room temperature. Tetra-n-butylammonium fluoride (5.6 mL, 5.6 mmol, 1M solution in THF) was added and the reaction stirred for 10 minutes at room temperature. The reaction mixture was concentrated in vacuo to an orange oil and was transferred to a separatory funnel and partitioned between ethyl acetate (200 mL) and water (50 mL). The aqueous layer was removed and the organic layer washed with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo to afford a dark yellow semi-solid. The product was purified by reverse phase chromatography using a gradient from 1:9 to 3:2 acetonitrile:water (0.1% TFA). Lyophilization of the desired fractions afforded 1.81 g (99% yield) of the desired product as a dark yellow powder. NMR (CDCl₃) δ 8.59 (s, 1H), 7.21 (m, 1H), 7.02 (m, 1H), 6.39 (m 2H), 4.56 (m, 1H), 4.29 (m, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.70 (m, 2H), 3.41 (m, 1H), 3.20 (m, 1H), 2.87 (m, 1H), 2.55 (s, 3H), 2.18 (m, 1H), 1.97-1.59 (m, 7H); MS (ESI+) for C₂₄H₃₀N₄O₅S m/z 487.1 (M+H)⁺.

N-(2,4-Dimethoxybenzyl)-8-[1-(hydroxymethyl)cyclohexyl]-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxamide

Desilylation of N-(2,4-dimethoxybenzyl)-2-(methylthio)-5-oxo-8-(1-{[(triisopropylsilyl)oxy]methyl}cyclohexyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxamide using General Procedure F afforded the desired product in 97% yield as a yellow powder. NMR (CDCl₃) δ 8.69 (s, 1H), 7.58 (m, 1H), 7.07 (m, 1H), 6.48 (m, 2H), 4.72 (m, 2H), 4.38 (m, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.31 (m, 1H), 2.99 (m, 1H), 2.81 (m, 1H), 2.64 (s, 3H), 2.11 (m, 3H), 1.94-1.58 (m, 7H); MS (ESI+) for C₂₅H₃₂N₄O₅S m/z 501.1 (M+H)⁺.

8-(2-Hydroxy-1,1-dimethylethyl)-N-(4-methoxybenzyl)-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxamide

Desilylation of 8-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-N-(2,4-dimethoxybenzyl)-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxamide using General Procedure F afforded the desired product in 98% yield as a yellow powder. NMR (CDCl₃) δ 8.61 (s, 1H), 7.51 (m, 1H), 7.01 (m, 1H), 6.37 (m, 2H), 4.72 (m, 1H), 4.65 (m, 1H), 4.26 (m, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.63 (m, 1H), 3.18 (m, 1H), 2.80 (m, 1H), 2.57 (s, 3H), 1.58 (s, 3H), 1.56 (s, 3H); MS (ESI+) for C₂₂H₂₈N₄O₅S m/z 461.4 (M+H)⁺.

N-(2,4-Dimethoxybenzyl)-8-(2-hydroxyethyl)-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxamide

Desilylation of N-(2,4-dimethoxybenzyl)-2-(methylthio)-5-oxo-8-{2-[(triisopropylsilyl)oxy]ethyl}-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxamide using General Procedure F afforded the desired product in 97% yield as a pale yellow powder. NMR (CDCl₃) δ 8.59 (s, 1H), 7.02 (m, 1H), 6.69 (m, 1H), 6.43 (m, 2H), 4.34 (m, 3H), 3.88 (m, 4H), 3.81 (s, 3H), 3.78 (s, 3H), 3.02 (m, 2H), 2.55 (s, 3H); MS (ESI+) for C₂₀H₂₄N₄O₅S m/z 432.9 (M+H)⁺.

N-[1-(Hydroxymethyl)cyclopentyl]-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxamide

Desilylation of 2-(methylthio)-5-oxo-N-(1-{[(triisopropylsilyl)oxy]methyl}cyclopentyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxamide using General Procedure F afforded the desired product in 31% yield as an off white powder. NMR (CDCl₃) δ 8.66 (s, 1H), 6.19 (bs, 1H), 5.97 (bs, 1H), 4.31 (m, 1H), 3.69 (s, 2H), 2.92 (m, 2H), 2.56 (s, 3H), 1.95-1.65 (m, 9H); MS (ESI+) for C₁₅H₂₀N₄O₃S m/z 337.0 (M+H)⁺.

General Procedure G

8′-(2,4-Dimethoxybenzyl)-2′-(methylthio)-6′,6a′,8′,9′-tetrahydrospiro[cyclopentane-1,10′-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine]-5′,7′-dione

N-(2,4-Dimethoxybenzyl)-8-[1-(hydroxymethyl)cyclopentyl]-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxamide (1.81 g, 3.72 mmol) was taken up in methylene chloride (30 mL) at room temperature. Triethylamine (1.3 mL, 9.3 mmol) was added followed by the rapid addition of methanesulfonyl chloride (0.43 mL, 5.6 mmol). The reaction mixture was stirred at room temperature for 30 minutes before being heated at reflux overnight. The solvent was removed in vacuo affording a brown semi-solid. The product was purified by reverse phase chromatography using a gradient from 1:9 to 3:2 acetonitrile:water (0.1% TFA). Lyophilization of the desired fractions gave 764 mg (44% yield) of the desired product as a light brown powder. NMR (CDCl₃) δ 8.49 (s, 1H), 7.13 (m, 1H), 6.43 (m, 2H), 5.49 (m, 1H), 4.37-4.16 (m, 4H), 3.81 (s, 3H), 3.80 (s, 3H), 3.29 (m, 1H), 2.95 (m, 1H), 2.82 (s, 3H), 2.41 (m, 1H), 1.99-1.52 (m, 7H); MS (ESI+) for C₂₄H₂₈N₄O₄S m/z 469.1 (M+H)⁺.

8′-(2,4-Dimethoxybenzyl)-2′-(methylthio)-6′,6a′,8′,9′-tetrahydrospiro[cyclohexane-1,10′-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine]-5′,7′-dione

Mesylation and cyclization of N-(2,4-dimethoxybenzyl)-8-[1-(hydroxymethyl)cyclohexyl]-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxamide using General Procedure G afforded the desired product in 73% yield as a white powder. NMR (MeOH-d₄) δ 8.48 (s, 1H), 7.14 (m, 1H), 6.43 (m, 1H), 6.39 (m, 1H), 5.61 (m, 1H), 4.31 (m, 1H), 4.21 (m, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 3.38 (m, 1H), 3.22 (m, 1H), 2.95 (m, 1H), 2.82 (s, 3H), 2.22 (m, 1H), 1.99-1.09 (m, 9H); MS (ESI+) for C₂₅H₃₀N₄O₄S m/z 483.1 (M+H)⁺.

8-(2,4-Dimethoxybenzyl)-10,10-dimethyl-2-(methylthio)-6,6a,9,10-tetrahydro-5H-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine-5,7(8H)-dione

Mesylation and cyclization of 8-(2-Hydroxy-1,1-dimethylethyl)-N-(4-methoxybenzyl)-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxamide using General Procedure G afforded the desired product in 82% yield as a yellow powder. NMR (CDCl₃) δ 8.45 (s, 1H), 7.14 (m, 1H), 6.40 (m, 2H), 5.56 (m, 1H), 4.40 (m, 1H), 4.31 (m, 2H), 4.13 (m, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.28 (m, 1H), 2.88 (m, 1H), 2.79 (s, 3H), 1.80 (s, 3H), 1.45 (s, 3H); MS (ESI+) for C₂₂H₂₆N₄O₄S m/z 443.5 (M+H)⁺.

8-(2,4-Dimethoxybenzyl)-2-(methylthio)-6,6a,9,10-tetrahydro-5H-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine-5,7(8H)-dione

Mesylation and cyclization of N-(2,4-dimethoxybenzyl)-8-(2-hydroxyethyl)-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxamide using General Procedure G afforded the desired product in 81% yield as a light brown powder. NMR (CDCl₃) δ 8.52 (s, 1H), 7.11 (m, 1H), 6.44 (m, 2H), 5.31 (m, 1H), 4.68-4.29 (m, 5H), 4.04 (m, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.20 (m, 1H), 3.01 (m, 1H), 2.82 (s, 3H); MS (ESI+) for C₂₀H₂₂N₄O₄S m/z 415.0 (M+H)⁺.

General Procedure H

2′-(Methylthio)-6′,6a′,8′,9′-tetrahydrospiro[cyclopentane-1,10′-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine]-5′,7′-dione

8′-(2,4-Dimethoxybenzyl)-2′-(methylthio)-6′,6a′,8′,9′-tetrahydrospiro[cyclopentane-1,10′-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine]-5′,7′-dione (764 mg, 1.63 mmol) was taken up in trifluoroacetic acid (10 mL) at room temperature under argon. The mixture was heated to 75° C. for 6 hours, cooled to room temperature and left to stir overnight. The solvent was removed in vacuo to afford a purple oil. The product was purified by reverse phase chromatography using a gradient from 100% water (0.1% TFA) to 1:1 acetonitrile:water (0.1% TFA). Lyophilization of the desired fractions afforded 117 mg (23% yield) of the desired product as a pale yellow powder. NMR (CDCl₃) δ 8.52 (s, 1H), 5.58 (m, 2H), 4.34 (bs 2H), 3.29 (m, 1H), 3.06 (m, 1H), 2.84 (s, 3H), 2.48 (m, 1H), 2.31 (m, 1H), 2.11-1.65 (m, 6H); MS (ESI+) for C₁₅H₁₈N₄O₂S m/z 319.0 (M+H)⁺.

2′-(Methylthio)-6′,6a′,8′,9′-tetrahydrospiro[cyclohexane-1,10′-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine]-5′,7′-dione

Removal of the dimethoxybenzyl group of 8′-(2,4-Dimethoxybenzyl)-2′-(methylthio)-6′,6a′,8′,9′-tetrahydrospiro[cyclohexane-1,10′-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine]-5′,7′-dione using General Procedure H afforded the desired product in 23% yield as a white powder. NMR (MeOH-d₄) δ 8.60 (s, 1H), 4.78 (m, 1H), 4.54 (m, 2H), 3.38 (m, 1H), 2.86 (s, 3H), 2.84 (m, 1H), 2.12-1.30 (m, 10H); MS (ESI+) for C₁₆H₂₀N₄O₂S m/z 333.1 (M+H)⁺.

10,10-Dimethyl-2-(methylthio)-6,6a,9,10-tetrahydro-5H-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine-5,7(8H)-dione

Removal of the dimethoxybenzyl group of 8-(2,4-dimethoxybenzyl)-10,10-dimethyl-2-(methylthio)-6,6a,9,10-tetrahydro-5H-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine-5,7(8H)-dione using General Procedure H afforded the desired product in 56% yield as a white powder. NMR (CDCl₃) δ 8.54 (s, 1H), 5.65 (m, 1H), 5.51 (bs, 1H), 4.31 (s, 2H), 3.23 (m, 1H), 3.04 (m, 1H), 2.85 (s, 3H), 1.78 (s, 3H), 1.68 (s, 3H); MS (ESI+) for C₁₃H₁₆N₄O₂S m/z 293.2 (M+H)⁺.

2-(Methylthio)-6,6a,9,10-tetrahydro-5H-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine-5,7(8H)-dione

Removal of the dimethoxybenzyl group of 8-(2,4-dimethoxybenzyl)-2-(methylthio)-6,6a,9,10-tetrahydro-5H-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine-5,7(8H)-dione using General Procedure H afforded the desired product in 21% yield as a brown powder. NMR (MeOH-d₄) δ 8.65 (s, 1H), 4.78-4.05 (m, 5H), 3.32 (m, 2H), 3.01 (m, 1H), 2.87 (s, 3H); MS (ESI+) for C₁₁H₁₂N₄O₂ m/z 265.0 (M+H)⁺.

General Procedure I

2′-{[5-(4-Methylpiperazin-1-yl)pyridin-2-yl]amino}-6′,6a′,8′,9′-tetrahydrospiro[cyclopentane-1,10′-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine]-5′,7′-dione

2′-(Methylthio)-6′,6a′,8′,9′-tetrahydrospiro[cyclopentane-1,10′-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine]-5′,7′-dione (117 mg, 0.367 mmol) was taken up in N,N-dimethylacetamide (4.0 mL, 43 mmol) at room temperature under argon. 5-(4-methylpiperazin-1-yl)pyridin-2-amine (100 mg, 0.55 mmol) was added and the reaction mixture was heated just to 150° C. and then immediately removed from the heat and cooled to room temperature. The product was purified by reverse phase chromatography using a gradient from 100% Water (0.1% TFA) to 1:1 acetonitrile:water (0.1% TFA). Lyophilization of the desired fractions afforded 11 mg (7% yield) of the desired product as an orange powder. NMR (MeOH-d₄) δ 8.54 (s, 1H); 8.06 (m, 1H), 7.85 (m, 1H), 7.69 (m, 1H), 4.69 (m, 1H), 4.39 (m, 2H), 3.95 (m, 2H), 3.69 (m, 2H), 3.39-3.15 (m, 5H), 3.02 (s, 3H), 2.77 (m, 1H), 2.21 (m, 1H), 2.09-1.67 (m, 7H); MS (ESI+) for C₂₄H₃₀N₈O₂ m/z 463.1 (M+H)⁺.

2′-{[5-(4-Methylpiperazin-1-yl)pyridin-2-yl]amino}-6′,6a′,8′,9′-tetrahydrospiro[cyclohexane-1,10′-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine]-5′,7′-dione

S_(N)Ar reaction using General Procedure I and 2′-(methylthio)-6′,6a′,8′,9′-tetrahydrospiro[cyclohexane-1,10′-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine]-5′,7′-dione afforded the desired product in 38% yield as a yellow powder. NMR (MeOH-d₄) δ 8.52 (s, 1H), 8.07 (m, 1H), 7.89 (bs, 1H), 7.71 (m, 1H), 4.71 (m, 1H), 4.40 (m, 2H), 3.94 (m, 2H), 3.68 (m, 2H), 3.35-3.22 (m, 5H), 3.02 (s, 3H), 2.73 (m, 1H), 2.02-1.25 (m, 10H); MS (ESI+) for C₂₅H₃₂N₈O₂ m/z 477.2 (M+H)⁺.

10,10-Dimethyl-2-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6,6a,9,10-tetrahydro-5H-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine-5,7(8H)-dione

S_(N)Ar reaction using General Procedure I and 10,10-dimethyl-2-(methylthio)-6,6a,9,10-tetrahydro-5H-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine-5,7(8H)-dione afforded the desired product in 10% yield as a yellow powder. NMR (MeOH-d₄) δ 8.52 (s, 1H), 8.05 (m, 2H), 7.86 (m, 1H), 7.67 (m, 1H), 4.66 (m, 1H), 4.33 (m, 2H), 3.93 (m, 2H), 3.68 (m, 2H), 3.38-3.21 (m, 5H), 3.01 (s, 3H), 2.72 (m, 1H), 1.65 (s, 3H), 1.54 (s, 3H); MS (ESI+) for C₂₂H₂₈N₈O₂ m/z 437.4 (M+H)⁺.

2-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6,6a,9,10-tetrahydro-5H-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine-5,7(8H)-dione

S_(N)Ar reaction using General Procedure I and 2-(methylthio)-6,6a,9,10-tetrahydro-5H-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine-5,7(8H)-dione afforded the desired product in 15% yield as an orange powder. NMR (DMSO-d₆) δ 8.41 (s, 1H), 8.05 (m, 1H), 7.93 (m, 1H), 7.82 (m, 1H), 4.59-4.34 (m, 3H), 4.03-3.84 (m, 4H), 3.49 (m, 2H), 3.30-3.09 (m, 6H), 2.80 (s, 3H), 2.80-2.67 (m, 2H); MS (ESI+) for C₂₀H₂₄N₈O₂ m/z 409.1 (M+H)⁺.

General Procedure J

2′-{[5-(4-Methylpiperazin-1-yl)pyridin-2-yl]amino}-6′,6a′,8′,9′-tetrahydro-7′H-dispiro[cyclohexane-1,10′-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine-5′,2″-[1,3]dithian]-7′-one

2′-{[5-(4-Methylpiperazin-1-yl)pyridin-2-yl]amino}-6′,6a′,8′,9′-tetrahydrospiro[cyclohexane-1,10′-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine]-5′,7′-dione (90.0 mg, 0.189 mmol) and 1,3-propanedithiol (0.0379 mL, 0.378 mmol) were taken up in toluene (5 mL) at room temperature under argon. p-Toluenesulfonic acid (0.02 g, 0.1 mmol) was then added. The reaction vessel was fitted with a condenser and the reaction mixture heated at reflux overnight. The reaction mixture was cooled to room temperature and the solvent removed in vacuo affording a thick dark yellow oil. The product was purified by reverse phase chromatography using a gradient from 100% water (0.1% TFA) to 3:2 acetonitrile:water (0.1% TFA). Lyophilization of the desired fractions afforded 35 mg (33% yield) of the desired product as a pale yellow powder. NMR (MeOH-d₄) δ 8.52 (s, 1H), 7.90 (m, 1H), 7.84 (m, 1H), 7.52 (m, 1H), 4.64 (m, 1H), 4.53 (m, 1H), 4.16 (m, 1H), 3.60 (m, 2H), 3.41-3.26 (m, 6H), 3.01 (s, 3H), 2.91 (m, 1H), 2.75 (m, 1H), 2.61 (m, 1H), 2.21 (m, 1H), 2.11 (m, 1H), 1.95-1.72 (m, 10H), 1.61 (m, 1H), 1.33 (m 2H); MS (ESI+) for C₂₈H₃₈N₈OS₂ m/z 567.1 (M+H)⁺.

10′,10′-Dimethyl-2′-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6′,6a′,9′,10′-tetrahydrospiro[1,3-dithiane-2,5′-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidin]-7′(8′H)-one

Dithiane formation using General Procedure J and 10,10-dimethyl-2-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6,6a,9,10-tetrahydro-5H-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine-5,7(8H)-dione afforded the desired product in 43% yield as an orange powder. NMR (MeOH-d₄) δ 8.53 (s, 1H), 7.88 (m, 1H), 7.82 (m, 1H), 7.47 (m, 1H), 4.47 (m, 1H), 4.41 (m, 1H), 4.16 (m, 1H), 3.92-3.15 (m, 11H), 3.00 (s, 3H), 2.90-2.81 (m, 3H), 2.21 (m, 1H), 1.87 (m, 1H), 1.60 (s, 3H), 1.48 (s, 3H); MS (ESI+) for C₂₅H₃₄N₈OS₂ m/z 527.1 (M+H)⁺.

General Procedure K

2′-{[5-(4-Methylpiperazin-1-yl)pyridin-2-yl]amino}-6′,6a′,8′,9′-tetrahydrospiro[cyclohexane-1,10′-pyrazino[1′,2′: 1,6]pyrido[2,3-d]pyrimidin]-7′(5′H)-one

2′-{[5-(4-Methylpiperazin-1-yl)pyridin-2-yl]amino}-6′,6a′, 8′,9′-tetrahydro-7′H-dispiro[cyclohexane-1,10′-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidine-5′,2″-[1,3]dithian]-7′-one (35 mg, 0.062 mmol) in ethanol (1 ml) was added to Raney nickel (1 mL of the aqueous slurry which was washed thrice with ethanol decanting off the ethanol after each washing) in ethanol (3 mL) under argon. The reaction mixture was heated to 45° C. for 30 minutes. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite® washing with ethanol. The solvent was removed in vacuo affording a yellow oil. The product was purified by reverse phase chromatography using a gradient from 100% water (0.1% TFA) to 3:2 acetonitrile:water (0.1% TFA). Lyophilization of the desired fractions afforded 4 mg (14% yield) of the desired product as a pale yellow powder. NMR (CDCl₃) δ 7.95 (m, 1H), 7.93 (s, 1H), 7.77 (m, 1H), 7.51 (m, 1H), 4.57 (m, 1H), 4.51 (m, 1H), 4.35 (m, 1H), 3.89 (m, 2H), 3.69 (m, 2H), 3.37 (m, 2H), 3.15 (m, 2H), 3.01 (s, 3H), 2.79 (m, 1H), 2.58 (m, 1H), 2.39 (m, 1H), 2.05-1.45 (m, 11H); MS (ESI+) for C₂₅H₃₄N₈O m/z 463.1 (M+H)⁺.

10,10-Dimethyl-2-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6,6a,9,10-tetrahydro-5H-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidin-7(8H)-one

Desulfurization using General Procedure K and 10′,10′-dimethyl-2′-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6′,6a′,9′,10′-tetrahydrospiro[1,3-dithiane-2,5′-pyrazino[1′,2′:1,6]pyrido[2,3-d]pyrimidin]-7′(8′H)-one afforded the desired product in 11% yield as a yellow powder. NMR (MeOH-d₄) δ 7.93 (m, 2H), 7.75 (m, 1H), 7.43 (m, 1H), 4.52 (m, 1H), 4.32 (m, 2H), 3.89 (m, 2H), 3.67 (m, 2H), 3.38 (m, 2H), 3.14 (m, 2H), 3.01 (s, 3H), 2.79 (m, 1H), 2.60 (m, 1H), 2.39 (m, 1H), 2.00 (m, 1H), 1.55 (s, 3H), 1.54 (s, 3H); MS (ESI+) for C₂₂H₃₀N₈O m/z 423.1 (M+H)⁺.

General Procedure L

(1-Aminocyclohexyl)methanol

2M Lithium tetrahydroaluminate in tetrahydrofuran (80.0 mL, 160 mmol) was charged into a 500 mL 3-necked round bottomed flask (oven-dried and cooled under argon) fitted with a magnetic stir bar and the solution was cooled to 0° C. under argon. 1-Aminocyclohexanecarboxylic acid (7.64 g, 53.3 mmol) is added portionwise over a period of 1 hour. At the end of the addition, the reaction mixture was diluted with tetrahydrofuran (60 mL), slowly warmed to room temperature, and then heated at reflux for 18 hours. The mixture was cooled to room temperature. The reaction mixture was further diluted with tetrahydrofuran (160 mL) and then cooled to 0° C. Saturated aqueous sodium carbonate (100 ml) was added very slowly keeping the internal temperature below 15° C. After the addition of the carbonate solution is complete, the ice bath was left to expire and the mixture slowly warmed to room temperature overnight. The reaction mixture was filtered thru a pad of Celite® washing with ethyl acetate (400 mL). The solvent was removed in vacuo to afford a wet oil which was taken up in methylene chloride (300 mL) and dried over sodium sulfate. Filtration and concentration of the solvent in vacuo affords 6.89 g (99% yield) of the desired product as a clear colorless oil. NMR (CDCl₃) 3.34 (s, 2H), 1.81 (bs, 3H), 1.51-1.32 (m, 10H); MS (ESI+) for C₇H₁₅NO m/z 130.0 (M+H)⁺.

(1-Aminocyclopentyl)methanol

Using General Procedure L on commercially available cycloleucine affords the desired product in 99% yield as a pale yellow oil. NMR (CDCl₃) 3.40 (s, 2H), 1.86-1.61 (m, 9H), 1.46-1.29 (m, 2H); MS (ESI+) for C₆H₁₃NO m/z 116.1 (M+H)⁺.

General Procedure M

1-{[(Triisopropylsilyl)oxy]methyl}cyclohexanamine

(1-Aminocyclohexyl)methanol (3.43 g, 26.5 mmol) was taken up in methylene chloride (80 mL) at room temperature under argon. Triethylamine (5.6 mL, 40 mmol) was added followed by the addition of triisopropylsilyl chloride (5.34 mL, 25.2 mmol). The reaction mixture was stirred at room temperature overnight during which time it became turbid. The reaction mixture was poured into a separatory funnel transferring with methylene chloride (100 mL). The organic layer was washed sequentially with water (40 mL×2) and brine (40 mL). The organic layer was dried over sodium sulfate, filtered and the solvent concentrated in vacuo to afford 6.68 g (93% yield) of the desired product as a clear pale yellow oil. NMR (CDCl₃) δ 3.49 (s, 2H), 1.75-1.25 (m, 10H), 1.16-1.06 (m, 21H); MS (ESI+) for C₁₁H₂₇NOSi m/z 203.2 (M+H)⁺.

1-{[(Triisopropylsilyl)oxy]methyl}cyclopentanamine

Following General Procedure M and using (1-aminocyclopentyl)methanol the desired product was obtained in 85% yield as a clear dark yellow oil. NMR (CDCl₃) δ 3.53 (s, 2H), 1.85-1.39 (m, 8H), 1.16-1.07 (m, 21H); MS (ESI+) for C₁₅H₃₃NOSi m/z 272.2 (M+H)⁺.

2-[(Triisopropylsilyl)oxy]ethanamine

Following General Procedure M and using commercially available ethanolamine the desired product was obtained in 99% yield as a clear pale yellow oil. NMR (CDCl₃) δ 3.56 (t, 2H, J=6.0 Hz), 2.94 (t, 2H, J=6.0 Hz), 1.09-0.99 (m, 21H); MS (ESI+) for C₁₁H₂₇NOSi m/z 217.2 (M+H)⁺.

1-{[tert-Butyl)dimethyl)silyl]oxy}-2-methylpropan-2-amine

Following General Procedure M and using commercially available 2-amino-2-methyl-1-propanol and using tert-butyldimethylsilyl chloride the desired product was obtained in 95% yield as a clear colorless oil. NMR (CDCl₃) δ 3.31 (s, 2H), 0.93 (s, 9H), 0.06 (s, 6H); MS (ESI+) for C₁₀H₂₅NOSi m/z 204.2 (M+H)⁺.

As exemplified in Scheme 10, compounds of Formula VI can be synthesized beginning with the aldehyde illustrated above. In Step 1, an alkyne can be treated with an organic solvent, and a base optionally at a reduced temperature and subsequently treated with an aldehyde according to methods known in the art. For example, the aldehyde in Step 1 can be treated with a base, for example, isopropylmagnesium chloride lithium chloride complex in an organic solvent, for example, tetrahydrofuran at about −15° C. and next treated with an aldehyde to generate an alkyne. In Step 2, a desired alkynyl alcohol can be treated with a base in an organic solvent at an elevated temperature to isomerize the desired alkynyl alcohol to a desired alkene. For example, a desired alkynyl alcohol can be treated with a base, such as triethylamine in an organic solvent, for example, 1,4-dioxane at an elevated temperature of about 60° C. to generate an alkene. In Step 3, a desired alkene can be treated with ammonia and a mixture of organic solvents to form a tert-butyl 2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylate according to methods known in the art. For example, an alkene can be treated with 0.5M ammonia and a mixture of organic solvents, for example, dioxane and acetonitrile to form a tert-butyl 2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylate. In Step 4, a desired ester can be treated with a desired acid and an organic solvent to generate a desired carboxylic acid according to methods known in the art. For example, a desired ester can be treated with a desired acid, for example, trifluoroacetic acid, to generate a carboxylic acid. In one embodiment, the organic solvent is dichloromethane. In Step 5, a desired acid can be treated with a desired amine, an organic solvent and a coupling reagent to form a desired amide according to methods known in the art. For example, a desired acid can be treated with a desired amine, an organic solvent, for example, N,N-dimethylformamide, and a coupling reagent, for example, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, to generate an amide. In Step 6, a silyl protected alcohol can be treated with a fluoride reagent and an organic solvent according to methods known in the art to generate a desired alcohol. For example, a silyl protected alcohol can be treated with a fluoride reagent, for example, tetrabutylammonium fluoride, and an organic solvent, for example, acetonitrile, to generate an alcohol. In step 7, a desired alcohol can be treated with a sulfonyl chloride to generate a desired mesylate according to methods known in the art. For example, an alcohol can be treated with a desired sulfonyl chloride, for example, methanesulfonyl chloride, to generate a mesylate. In one embodiment, an amine spontaneously reacts with said mesylate to generate a cyclic amide. In Step 8, a desired thiol can be treated with a desired amine and an organic solvent at an elevated temperature to generate a desired amine according to methods known in the art. For example, a thiol can be treated with an amine, for example, 5-(4-methylpiperazin-1-yl)pyridin-2-amine, and an organic solvent, for example, N,N-dimethylacetamide, at an elevated temperature of about 150° C. to generate an amine. The compound 5-(4-methylpiperazin-1-yl)pyridin-2-amine can be prepared as disclosed in U.S. Pat. No. 8,598,186 to Tavares and Strum.

As exemplified in Scheme 11, compounds of Formula VI can be synthesized beginning with the aldehyde illustrated above. In Step 1, an alkyne can be treated with an organic solvent, and a base optionally at a reduced temperature and subsequently treated with an aldehyde according to methods known in the art. For example, the aldehyde in Step 1 can be treated with a base, for example, isopropylmagnesium chloride lithium chloride complex in an organic solvent, for example, tetrahydrofuran at about −15° C. and next treated with an aldehyde to generate an alkyne. In Step 2, a desired alkynyl alcohol can be treated with a base in an organic solvent at an elevated temperature to isomerize the desired alkynyl alcohol to a desired alkene. For example, a desired alkynyl alcohol can be treated with a base, such as triethylamine in an organic solvent, for example, 1,4-dioxane at an elevated temperature of about 60° C. to generate an alkene. In Step 3, a desired alkene can be treated with ammonia and a mixture of organic solvents to form a tert-butyl 2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylate according to methods known in the art. For example, an alkene can be treated with 0.5M ammonia and a mixture of organic solvents, for example, dioxane and acetonitrile to form a tert-butyl 2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-7-carboxylate. In Step 4, an amine can be treated with a base, an organic solvent, and a cyclic sulfamidate to form an amine according to methods known in the art. For example, a desired amine can be treated with a base, for example, triethylamine, an organic solvent, for example, N,N-dimethylformamide, and a cyclic sulfamidate to form an amine. In Step 5, a protected amine can be treated with an organic acid to form an amine that can subsequently form a cyclic amide according to methods known in the art. For example, a protected amine can be treated with an organic acid, for example, trifluoroacetic acid, and subsequently react with an ester to form a cyclic amide.

EXAMPLES Example 1 Synthesis of Compound 2 (Scheme 1)

Compound 2 is synthesized according to the method of A. Haidle et al., See, WO 2009/152027 entitled “5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one derivatives for MARK inhibition.”

Example 2 Synthesis of Compound 3 (Scheme 1)

Step 1: A round-bottomed flask inerted with a nitrogen atmosphere is charged with Compound 2, ethanol, and lithium borohydride at ambient temperature. The reaction is stirred at ambient temperature and monitored by thin layer chromatography (TLC) or HPLC. Once Compound 2 can no longer be detected, the reaction is quenched with an aqueous acid such as aqueous hydrochloric acid, diluted with ethyl acetate and the layers separated. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product, a primary alcohol, is purified by silica gel column chromatography eluting with a hexane-ethyl acetate gradient and used directly in the next step.

Step 2: A round-bottomed flask inerted with a nitrogen atmosphere is charged with the primary alcohol prepared in step 1, DMF and phosphorus tribromide. The reaction is stirred at ambient temperature and monitored by thin layer chromatography (TLC) or HPLC. Once the primary alcohol can no longer be detected, the reaction is quenched with brine and diluted with toluene. The layers are separated and the toluene layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The bromide is purified by silica gel column chromatography eluting with a hexane-ethyl acetate gradient.

Example 3 Synthesis of Compound 5 (Scheme 1)

A round-bottomed flask inerted with a nitrogen atmosphere is charged with tetrahydrofuran and the lactam 4, described below. The reaction is cooled to −78° C. and lithium diisopropylamide solution (2M in THF/heptane/ethyl benzene) is added dropwise. To the resulting enolate is added Compound 3, dropwise, and the reaction is allowed to warm to room temperature overnight. The reaction is diluted with saturated brine and the layers are separated. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product is purified by silica gel column chromatography eluting with a dichloromethane-methanol gradient.

Example 4 Synthesis of Compound 6 (Scheme 1)

A round-bottomed flask is charged with Compound 5 and an aqueous acid, for example a pH=1 HCl solution. The reaction is allowed to stir at room temperature until starting material is no longer detected by thin layer chromatography or HPLC. The reaction is neutralized with solid K₂CO₃ and diluted with dichloromethane. The layers are separated, the organic layer dried over anhydrous magnesium sulfate, filtered and concentrated. Compound 6 is purified by silica gel column chromatography eluting with a dichloromethane-methanol gradient.

Example 5 Synthesis of Compound 7 (Scheme 1)

A round-bottomed flask inerted with a nitrogen atmosphere is charged with Compound 6, ethanol and DBU (10 eq). The reaction is monitored by thin layer chromatography or HPLC. Note: The reaction can be heated at reflux if necessary. Once Compound 6 is no longer detected, the reaction is concentrated in vacuo. The lactam 7 is purified by silica gel column chromatography eluting with a dichloromethane-methanol gradient.

Example 6 Synthesis of Compound 8 (Scheme 1)

A round-bottomed flask inerted with a nitrogen atmosphere is charged with Compound 7, meta-chloroperoxybenzoic acid, an organic solvent and stirred at ambient temperature. The reaction is monitored by thin layer chromatography or HPLC. Once Compound 7 is no longer detected, the reaction is concentrated in vacuo. Compound 8 is purified by silica gel column chromatography eluting with a dichloromethane-methanol gradient.

Example 7 Synthesis of Compound 10 (Scheme 1)

The tricyclic lactam 8 is combined with an amine (9, 0.9 eq) and an organic solvent such as tetrahydrofuran. A strong base such as lithium hexamethyldisilazane is added and the reaction is stirred until lactam 8 is no longer detected by either thin layer chromatography or HPLC. The reaction is concentrated in vacuo. The product is purified by silica gel column chromatography eluting with a dichloromethane-methanol gradient.

Alternatively, a CEM Discovery microwave vessel is charged with the tricyclic lactam 8, N-methyl-2-pyrrolidone (NMP), Hunig's base, and amine 9 (0.9 eq). The reaction is heated at 150° C. for 1-4 hours while being monitored by TLC. Once the tricyclic lactam 8 is no longer detected by TLC or HPLC, the reaction is concentrated in vacuo. The product is purified by silica gel column chromatography eluting with a dichloromethane-methanol gradient.

Example 8 Synthesis of Compound 11 (Scheme 2)

Compound 7 is treated with an oxidizing agent such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in an organic solvent to generate the alkene intermediate 12.

Example 9 Synthesis of Compound 14 (Scheme 2)

The sulfone intermediate 12 is combined with an amine (13, 0.9 eq) in an organic solvent such as tetrahydrofuran. An organic base such as lithium hexamethyldisilazane is added and the reaction is stirred until sulfone intermediate 12 can no longer be detected by thin layer chromatography or HPLC. The product is purified by silica gel column chromatography eluting with a dichloromethane-methanol gradient.

Alternatively, a CEM Discovery microwave vessel is charged with the sulfone intermediate 12, N-methyl-2-pyrrolidone (NMP), Hunig's base, and amine 13 (0.9 eq). The reaction is heated at 150° C. for 1-4 hours while being monitored by TLC. Once the sulfone intermediate 12 is no longer detected by TLC or HPLC, the reaction is concentrated in vacuo. The product is purified by silica gel column chromatography eluting with a dichloromethane-methanol gradient.

Example 10 Synthesis of Compound 4

Step 1: Synthesis of Compound 15 (Scheme 3)

Compound 15 is synthesized according to the method of Arigon, J., See, US 2013/0289031, entitled “Pyrimidinone derivatives, preparation thereof and pharmaceutical use thereof.”

Step 2: Synthesis of Compound 16 (Scheme 3)

A round-bottomed flask inerted with a nitrogen atmosphere is charged with Compound 15, dichloromethane and triethylamine (1.5 eq). The reaction is cooled to 0° C. and Boc anhydride (1.5 eq) is added. The reaction is allowed to stir at room temperature until Compound 15 is no longer detected by thin layer chromatography or HPLC. The reaction is concentrated in vacuo. The product is purified by silica gel column chromatography eluting with a hexane-ethyl acetate gradient.

Step 3: Synthesis of Compound 17 (Scheme 3)

A round-bottomed flask inerted with a nitrogen atmosphere is charged with Compound 16, acetonitrile and a base such as potassium carbonate. Methyl chloroacetate is added dropwise. The reaction is allowed to stir at room temperature until Compound 16 is no longer detected by thin layer chromatography or HPLC. The reaction is concentrated in vacuo. The product is purified by silica gel column chromatography eluting with a hexane-ethyl acetate gradient.

Step 4: Synthesis of Compound 18 (Scheme 3)

Compound 17 is dissolved in a solution comprising 3M HCl in methanol and the reaction is stirred at ambient temperature. Note: the reaction can be heated at a temperature of about 25° C. to about 60° C. to accelerate the reaction rate. Once the starting material is no longer detected by thin layer chromatography, the reaction is concentrated in vacuo. The product is purified by silica gel column chromatography using a dichloromethane-methanol gradient

Step 5: Synthesis of Compound 19 (Scheme 3)

A round-bottomed flask inerted with a nitrogen atmosphere is charged with Compound 18, dichloromethane, and diisopropylethylamine (1.2 eq). Chloromethyl methyl ether (MOM-Cl, 1.2 eq) is added dropwise. The reaction is allowed to stir at room temperature and monitored by TLC. Once the starting material is no longer detected by thin layer chromatography, the reaction is quenched with saturated brine solution. The organic layer is separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product is purified by silica gel column chromatography using a dichloromethane-methanol gradient.

Step 6: Synthesis of Compound 4

A round-bottomed flask inerted with a nitrogen atmosphere is charged with anhydrous tetrahydrofuran and Compound 19. The reaction is cooled to −78° C. Sodium bis(trimethylsilyl)amide (1M in THF, 1.1 eq) is added dropwise. Chloromethyl methyl ether (MOM-Cl, 1.2 eq) is added dropwise with stirring and the reaction is allowed to warm to room temperature overnight. The reaction is quenched with saturated brine solution and the layers are separated. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product is purified by silica gel column chromatography using a dichloromethane-methanol gradient.

Example 11 Synthesis of Compound 25 (Scheme 5)

Compound 20 is commercially available. Compound 25 is synthesized according to the synthetic methodology disclosed in Example 10.

Example 12 Synthesis of Compound 31 (Scheme 6)

Compound 31 is synthesized according to the synthetic methodology disclosed in Example 10.

Example 13 Synthesis of Compound 33 (Scheme 7)

Step 1: Synthesis of Compound 32

Compound 32, 5-morpholinopyrid-2-amine, is synthesized according to Tavares, F. X. and Strum, J. C., See, U.S. Pat. No. 8,598,186, entitled “CDK Inhibitors”.

Step 2: Synthesis of Compound 33

The sulfone intermediate 8 is diluted with a suitable solvent such as tetrahydrofuran and an organic base such as lithium hexamethyldisilazane is added. Compound 32, 5-morpholinopyrid-2-amine is added and the reaction is stirred until sulfone intermediate 8 can no longer be detected by thin layer chromatography or HPLC. The product is purified by silica gel column chromatography eluting with a dichloromethane-methanol gradient.

Alternatively, a CEM Discovery microwave vessel is charged with the sulfone intermediate 8, N-methyl-2-pyrrolidone (NMP), Hunig's base, and 5-morpholinopyrid-2-amine (0.9 eq). The reaction is heated at 150° C. for 1-4 hours while being monitored by TLC. Once the sulfone intermediate 8 is no longer detected by TLC or HPLC, the reaction is concentrated in vacuo. The product is purified by silica gel column chromatography eluting with a dichloromethane-methanol gradient.

Example 14 Synthesis of Compound 34 (Scheme 8)

Step 1: Synthesis of Compound 32

Compound 32, 5-morpholinopyrid-2-amine, is synthesized according to Tavares, F. X. and Strum, J. C., See, U.S. Pat. No. 8,598,186, entitled “CDK Inhibitors”.

Step 2: Synthesis of Compound 34

The sulfone intermediate 12 is combined with a suitable solvent such as tetrahydrofuran and an organic base such as lithium hexamethyldisilazane. Compound 32 is added and the reaction is stirred until sulfone intermediate 12 can no longer be detected by thin layer chromatography or HPLC. The product is purified by silica gel column chromatography eluting with a dichloromethane-methanol gradient.

Alternatively, a CEM Discovery microwave vessel is charged with the sulfone intermediate 12, N-methyl-2-pyrrolidone (NMP), Hunig's base, and 5-morpholinopyrid-2-amine (0.9 eq). The reaction is heated at 150° C. for 1-4 hours while being monitored by TLC. Once the sulfone intermediate 12 is no longer detected by TLC or HPLC, the reaction is concentrated in vacuo. The product is purified by silica gel column chromatography eluting with a dichloromethane-methanol gradient.

Example 15 Preparation of a Formula V compound

Step 1: Compound 7 is Boc protected according to the method of A. Sarkar et al. (JOC, 2011, 76, 7132-7140).

Step 2: Boc-protected Compound 7 is treated with 5 mol % NiCl₂(Ph₃)₂, 0.1 eq triphenylphosphine, 3 eq Mn, 0.1 eq tetraethylammonium iodide, in DMI under CO₂ (1 atm) at 25° C. for 20 hours to convert the methyl thiol derivative into the carboxylic acid.

Step 3: The carboxylic acid from Step 2 is converted to the corresponding acid chloride using standard conditions.

Step 4: The acid chloride from Step 3 is reacted with N-methyl piperazine to generate the corresponding amide.

Step 5: The amide from Step 4 is deprotected using trifluoroacetic acid in methylene chloride to generate the target compound. The product is purified by silica gel column chromatography eluting with a dichloromethane-methanol gradient.

Compounds with various R⁸, R¹ and Z definitions may be reacted with sodium hydride and an alkyl halide or other halide to insert the desired R substitution prior to reaction with an amine to produce the desired product of Formulae I, II, III, IV, V, or VI.

Example 16 Inhibition of Cellular Proliferation

SupT1 (human T cell lymphoblastic leukemia) cells and Daudi (human B-lymphoblastoid cell from Burkitt's Lymphoma patient) cells are seeded in Costar (Tewksbury, Mass.) 3093 96 well tissue culture treated white walled/clear bottom plates. A nine point dose response dilution series from 10 uM to 1 nM is performed and cell viability is determined after four days using the CellTiter-Glo® assay (CTG; Promega, Madison, Wis., United States of America) following the manufacturer's recommendations. Plates are read on a BioTek (Winooski, Vt.) Syngergy2 multi-mode plate reader. The Relative Light Units (RLU) are plotted as a result of variable molar concentration and data is analyzed using Graphpad (LaJolla, Calif.) Prism 5 statistical software to determine the IC₅₀ for each compound. The tricyclic lactam compounds listed in Table 1 are tested for the inhibition of cellular proliferation using SupT1 (human T-cell lymphoblastic leukemia) and Daudi (human B-lymphoblastoid cell from Burkitt's Lymphoma patient) cells.

This specification has been described with reference to embodiments of the invention. The invention has been described with reference to assorted embodiments, which are illustrated by the accompanying Examples. The invention can, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Given the teaching herein, one of ordinary skill in the art will be able to modify the invention for a desired purpose and such variations are considered within the scope of the invention. 

We claim:
 1. A method for the treatment of abnormal T-cell proliferation that comprises administering an effective amount of a compound of Formula I, II, III, IV, or V to a host in need thereof:

wherein: Z is —(CH₂)_(x)— wherein x is 1, 2, 3 or 4 or —O—(CH₂)_(z)— wherein z is 2, 3 or 4; each X is independently CH or N; each X′ is independently CH or N; X″ is independently CH₂, S or NH, arranged such that the moiety is a stable 5-membered ring; R, R⁸, and R¹¹ are independently H, C₁-C₃ alkyl or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene)_(m)-C₃-C₈ cycloalkyl, -(alkylene)_(m)-aryl, -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valance, and wherein two R^(x) groups bound to the same or adjacent atoms may optionally combine to form a ring; each R¹ is independently aryl, alkyl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally includes O or N heteroatoms in place of a carbon in the chain and two R¹'s on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle; y is 0, 1, 2, 3 or 4; R² is -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-C(O)—O-alkyl; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valance, and wherein two R^(x) groups bound to the same or adjacent atom may optionally combine to form a ring and wherein m is 0, 1 or 2 and n is 0, 1 or 2; R³ and R⁴ at each occurrence are independently: (i) hydrogen or (ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valance, and wherein two R^(x) groups bound to the same or adjacent atom may optionally combine to form a ring; or R³ and R⁴ together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R^(x) groups as allowed by valance, and wherein two R^(x) groups bound to the same or adjacent atom may optionally combine to form a ring; R⁵ and R⁵* at each occurrence is: (i) hydrogen or (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valance; R^(x) at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene)_(m)-OR⁵, -(alkylene)_(m)-O-alkylene-OR⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-CN, -(alkylene)_(m)-C(O)—R⁵, -(alkylene)_(m)-C(S)—R⁵, -(alkylene)_(m)-C(O)—OR⁵, -(alkylene)_(m)-O—C(O)—R⁵, -(alkylene)_(m)-C(S)—OR⁵, -(alkylene)_(m)-C(O)-(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(S)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(S)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—R⁵, -(alkylene)_(m)-N(R³)—C(S)—R⁵, -(alkylene)_(m)-O—C(O)—NR³R⁴, -(alkylene)_(m)-O—C(S)—NR³R⁴, -(alkylene)_(m)-SO₂—NR³R⁴, -(alkylene)_(m)-N(R³)—SO₂—R⁵, -(alkylene)_(m)-N(R³)—SO₂—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—OR⁵)-(alkylene)_(m)-N(R³)—C(S)—OR⁵, or -(alkylene)_(m)-N(R³)—SO₂—R⁵; wherein: said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more -(alkylene)_(m)-CN, -(alkylene)_(m)-OR⁵*, -(alkylene)_(m)-S(O)_(n)—R⁵*, -(alkylene)_(m)-NR³*R⁴*, -(alkylene)_(m)-C(O)—R⁵*, -(alkylene)_(m)-C(═S)R⁵*, -(alkylene)_(m)-C(═O)OR⁵*, -(alkylene)_(m)-OC(═O)R⁵*, -(alkylene)_(m)-C(S)—OR⁵*, -(alkylene)_(m)-C(O)—NR³*R⁴*, -(alkylene)_(m)-C(S)—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(O)—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(S)—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(O)—R⁵*, -(alkylene)_(m)-N(R³*)—C(S)—R⁵*, -(alkylene)_(m)-O—C(O)—NR³*R⁴*, -(alkylene)_(m)-O—C(S)—NR³*R⁴*, -(alkylene)_(m)-SO₂—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—SO₂—R⁵*, -(alkylene)_(m)-N(R³*)—SO₂—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(O)—OR⁵*, -(alkylene)_(m)-N(R³*)—C(S)—OR⁵*, or -(alkylene)_(m)-N(R³*)—SO₂—R⁵*, n is 0, 1 or 2, and m is 0, 1 or 2; R³* and R⁴* at each occurrence are independently: (i) hydrogen or (ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valance; or R³* and R⁴* together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R^(x) groups as allowed by valance; and R⁶ is H or lower alkyl, -(alkylene)m-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valance, and wherein two R^(x) groups bound to the same or adjacent atoms may optionally combine to form a ring; and R¹⁰ is (i) NHR^(A), wherein R^(A) is unsubstituted or substituted C₁-C₈ alkyl, cycloalkylalkyl, or -TT-RR, C₁-C₈ cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O, and S; TT is an unsubstituted or substituted C₁-C₈ alkyl or C₃-C₈ cycloalkyl linker; and RR is a hydroxyl, unsubstituted or substituted C₁-C₆ alkoxy, amino, unsubstituted or substituted C₁-C₆ alkylamino, unsubstituted or substituted di-C₁-C₆ alkylamino, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀ carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; or (ii) —C(O)—R¹² or —C(O)O—R¹³, wherein R¹² is NHR^(A) or R^(A) and R¹³ is R^(A); when compounds comprise a double bond in the 6-membered ring fused to the pyrimidine ring, two R⁸ groups are present and are as defined above; when compounds do not comprise a double bond in the 6-membered ring fused to the pyrimidine ring, four R⁸ groups are present and are as defined above; or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1, wherein the compound is selected from the group consisting of: Structure Reference Structure A

B

C

D

E

F

G

H

I

J

K

L

M

N

O

P

Q

R

S

T

U

V

W

X

Y

Z

AA

BB

CC

DD

EE

FF

GG

HH

II

JJ

KK

LL

MM

NN

OO

PP

QQ

RR

SS

TT

UU

VV

WW

XX

YY

ZZ

AAA

BBB

CCC

DDD

EEE

FFF

GGG

HHH

III

JJJ

KKK

LLL

MMM

NNN

OOO

PPP

QQQ

RRR

SSS

TTT

UUU

VVV

WWW

XXX


3. The method of claim 2, wherein the compound is selected from the group consisting of Compound A through Compound Z, or its pharmaceutically acceptable salt.
 4. The method of claim 2, wherein the compound is selected from the group consisting of Compound AA through ZZ, or its pharmaceutically acceptable salt.
 5. The method of claim 2, wherein the compound is selected from the group consisting of Compound AAA through XXX, or its pharmaceutically acceptable salt.
 6. The method of claim 1, wherein the abnormal T-cell proliferation is T-cell lymphoma.
 7. The method of claim 1, wherein the abnormal T-cell proliferation is T-cell leukemia.
 8. The method of claim 6, wherein the abnormal T-cell lymphoma is Hodgkin Lymphoma.
 9. The method of claim 6, wherein the T-cell lymphoma is Non-Hodgkin Lymphoma.
 10. The method of claim 1, wherein the compound is conjugated to a targeting agent.
 11. The method of claim 10, wherein the targeting agent is an antibody or antibody fragment.
 12. The method of claim 1, wherein the compound is conjugated to a radioisotope.
 13. The method of claim 1, wherein the host is a human.
 14. The method of claim 6, wherein the host is a human.
 15. The method of claim 7, wherein the host is a human.
 16. A method for the treatment of abnormal B-cell proliferation that comprises administering an effective amount of a compound of Formula I, II, III, IV, or V to a host in need thereof:

wherein: Z is —(CH₂)_(x)— wherein x is 1, 2, 3 or 4 or —O—(CH₂)_(z)— wherein z is 2, 3 or 4; each X is independently CH or N; each X′ is independently CH or N; X″ is independently CH₂, S or NH, arranged such that the moiety is a stable 5-membered ring; R, R⁸, and R¹¹ are independently H, C₁-C₃ alkyl or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene)_(m)-C₃-C₈ cycloalkyl, -(alkylene)_(m)-aryl, -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valance, and wherein two R^(x) groups bound to the same or adjacent atoms may optionally combine to form a ring; each R¹ is independently aryl, alkyl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally includes O or N heteroatoms in place of a carbon in the chain and two R¹'s on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle; y is 0, 1, 2, 3 or 4; R² is -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-C(O)—O-alkyl; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valance, and wherein two R^(x) groups bound to the same or adjacent atom may optionally combine to form a ring and wherein m is 0, 1 or 2 and n is 0, 1 or 2; R³ and R⁴ at each occurrence are independently: (i) hydrogen or (ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valance, and wherein two R^(x) groups bound to the same or adjacent atom may optionally combine to form a ring; or R³ and R⁴ together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R^(x) groups as allowed by valance, and wherein two R^(x) groups bound to the same or adjacent atom may optionally combine to form a ring; R⁵ and R⁵* at each occurrence is: (i) hydrogen or (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valance; R^(x) at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene)_(m)-OR⁵, -(alkylene)_(m)-O-alkylene-OR⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-CN, -(alkylene)_(m)-C(O)—R⁵, -(alkylene)_(m)-C(S)—R⁵, -(alkylene)_(m)-C(O)—OR⁵, -(alkylene)_(m)-O—C(O)—R⁵, -(alkylene)_(m)-C(S)—OR⁵, -(alkylene)_(m)-C(O)-(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(S)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(S)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—R⁵, -(alkylene)_(m)-N(R³)—C(S)—R⁵, -(alkylene)_(m)-O—C(O)—NR³R⁴, -(alkylene)_(m)-O—C(S)—NR³R⁴, -(alkylene)_(m)-SO₂—NR³R⁴, -(alkylene)_(m)-N(R³)—SO₂—R⁵, -(alkylene)_(m)-N(R³)—SO₂—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—OR⁵) -(alkylene)_(m)-N(R³)—C(S)—OR⁵, or -(alkylene)_(m)-N(R³)—SO₂—R⁵; wherein: said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more -(alkylene)_(m)-CN, -(alkylene)_(m)-OR⁵*, -(alkylene)_(m)-S(O)_(n)—R⁵*, -(alkylene)_(m)-NR³*R⁴*, -(alkylene)_(m)-C(O)—R⁵*, -(alkylene)_(m)-C(═S)R⁵*, -(alkylene)_(m)-C(═O)OR⁵*, -(alkylene)_(m)-OC(═O)R⁵*, -(alkylene)_(m)-C(S)—OR⁵*, -(alkylene)_(m)-C(O)—NR³*R⁴*, -(alkylene)_(m)-C(S)—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(O)—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(S)—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(O)—R⁵*, -(alkylene)_(m)-N(R³*)—C(S)—R⁵*, -(alkylene)_(m)-O—C(O)—NR³*R⁴*, -(alkylene)_(m)-O—C(S)—NR³*R⁴*, -(alkylene)_(m)-SO₂—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—SO₂—R⁵*, -(alkylene)_(m)-N(R³*)—SO₂—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(O)—OR⁵*, -(alkylene)_(m)-N(R³*)—C(S)—OR⁵*, or -(alkylene)_(m)-N(R³*)—SO₂—R⁵*, n is 0, 1 or 2, and m is 0, 1 or 2; R³* and R⁴* at each occurrence are independently: (i) hydrogen or (ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valance; or R³* and R⁴* together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R^(x) groups as allowed by valance; and R⁶ is H or lower alkyl, -(alkylene)m-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valance, and wherein two R^(x) groups bound to the same or adjacent atoms may optionally combine to form a ring; and R¹⁰ is (i) NHR^(A), wherein R^(A) is unsubstituted or substituted C₁-C₈ alkyl, cycloalkylalkyl, or -TT-RR, C₁-C₈ cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O, and S; TT is an unsubstituted or substituted C₁-C₈ alkyl or C₃-C₈ cycloalkyl linker; and RR is a hydroxyl, unsubstituted or substituted C₁-C₆ alkoxy, amino, unsubstituted or substituted C₁-C₆ alkylamino, unsubstituted or substituted di-C₁-C₆ alkylamino, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀ carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; or (ii) —C(O)—R¹² or —C(O)O—R¹³, wherein R¹² is NHR^(A) or R^(A) and R¹³ is R^(A); when compounds comprise a double bond in the 6-membered ring fused to the pyrimidine ring, two R⁸ groups are present and are as defined above; when compounds do not comprise a double bond in the 6-membered ring fused to the pyrimidine ring, four R⁸ groups are present and are as defined above; or a pharmaceutically acceptable salt thereof.
 17. The method of claim 16, wherein the compound is selected from the group consisting of: Structure Reference Structure A

B

C

D

E

F

G

H

I

J

K

L

M

N

O

P

Q

R

S

T

U

V

W

X

Y

Z

AA

BB

CC

DD

EE

FF

GG

HH

II

JJ

KK

LL

MM

NN

OO

PP

QQ

RR

SS

TT

UU

VV

WW

XX

YY

ZZ

AAA

BBB

CCC

DDD

EEE

FFF

GGG

HHH

III

JJJ

KKK

LLL

MMM

NNN

OOO

PPP

QQQ

RRR

SSS

TTT

UUU

VVV

WWW

XXX


18. The method of claim 17, wherein the Compound is selected from the group consisting of Compound A through Compound Z, or its pharmaceutically acceptable salt.
 19. The method of claim 17, wherein the compound is selected from the group consisting of Compound AA through ZZ, or its pharmaceutically acceptable salt.
 20. The method of claim 17, wherein the compound is selected from the group consisting of Compound AAA through XXX, or its pharmaceutically acceptable salt.
 21. The method of claim 16, wherein the compound is conjugated to a targeting agent.
 22. The method of claim 21, wherein the targeting agent is an antibody or antibody fragment.
 23. The method of claim 16, wherein the compound is conjugated to a radioisotope.
 24. The method of claim 16, wherein the host is a human.
 25. A method for the treatment of an autoimmune disease that comprises administering an effective amount of a compound of Formula I, II, III, IV, or V to a host in need thereof:

wherein: Z is —(CH₂)_(x)— wherein x is 1, 2, 3 or 4 or —O—(CH₂)_(z)— wherein z is 2, 3 or 4; each X is independently CH or N; each X′ is independently CH or N; X″ is independently CH₂, S or NH, arranged such that the moiety is a stable 5-membered ring; R, R⁸, and R¹¹ are independently H, C₁-C₃ alkyl or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene)_(m)-C₃-C₈ cycloalkyl, -(alkylene)_(m)-aryl, -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valance, and wherein two R^(x) groups bound to the same or adjacent atoms may optionally combine to form a ring; each R¹ is independently aryl, alkyl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally includes O or N heteroatoms in place of a carbon in the chain and two R¹'s on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle; y is 0, 1, 2, 3 or 4; R² is -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-C(O)—O-alkyl; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valance, and wherein two R^(x) groups bound to the same or adjacent atom may optionally combine to form a ring and wherein m is 0, 1 or 2 and n is 0, 1 or 2; R³ and R⁴ at each occurrence are independently: (i) hydrogen or (ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valance, and wherein two R^(x) groups bound to the same or adjacent atom may optionally combine to form a ring; or R³ and R⁴ together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R^(x) groups as allowed by valance, and wherein two R^(x) groups bound to the same or adjacent atom may optionally combine to form a ring; R⁵ and R⁵* at each occurrence is: (i) hydrogen or (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valance; R^(x) at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene)_(m)-OR⁵, -(alkylene)_(m)-O-alkylene-OR⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-CN, -(alkylene)_(m)-C(O)—R⁵, -(alkylene)_(m)-C(S)—R⁵, -(alkylene)_(m)-C(O)—OR⁵, -(alkylene)_(m)-O—C(O)—R⁵, -(alkylene)_(m)-C(S)—OR⁵, -(alkylene)_(m)-C(O)-(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(S)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(S)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—R⁵, -(alkylene)_(m)-N(R³)—C(S)—R⁵, -(alkylene)_(m)-O—C(O)—NR³R⁴, -(alkylene)_(m)-O—C(S)—NR³R⁴, -(alkylene)_(m)-SO₂—NR³R⁴, -(alkylene)_(m)-N(R³)—SO₂—R⁵, -(alkylene)_(m)-N(R³)—SO₂—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—OR⁵)-(alkylene)_(m)-N(R³)—C(S)—OR⁵, or -(alkylene)_(m)-N(R³)—SO₂—R⁵; wherein: said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more -(alkylene)_(m)-CN, -(alkylene)_(m)-OR⁵*, -(alkylene)_(m)-S(O)_(n)—R⁵*, -(alkylene)_(m)-NR³*R⁴*, -(alkylene)_(m)-C(O)—R⁵*, -(alkylene)_(m)-C(═S)R⁵*, -(alkylene)_(m)-C(═O)OR⁵*, -(alkylene)_(m)-OC(═O)R⁵*, -(alkylene)_(m)-C(S)—OR⁵*, -(alkylene)_(m)-C(O)—NR³*R⁴*, -(alkylene)_(m)-C(S)—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(O)—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(S)—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(O)—R⁵*, -(alkylene)_(m)-N(R³*)—C(S)—R⁵*, -(alkylene)_(m)-O—C(O)—NR³*R⁴*, -(alkylene)_(m)-O—C(S)—NR³*R⁴*, -(alkylene)_(m)-SO₂—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—SO₂—R⁵*, -(alkylene)_(m)-N(R³*)—SO₂—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(O)—OR⁵*, -(alkylene)_(m)-N(R³*)—C(S)—OR⁵*, or -(alkylene)_(m)-N(R³*)—SO₂—R⁵*, n is 0, 1 or 2, and m is 0, 1 or 2; R³* and R⁴* at each occurrence are independently: (i) hydrogen or (ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valance; or R³* and R⁴* together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R^(x) groups as allowed by valance; and R⁶ is H or lower alkyl, -(alkylene)m-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valance, and wherein two R^(x) groups bound to the same or adjacent atoms may optionally combine to form a ring; and R¹⁰ is (i) NHR^(A), wherein R^(A) is unsubstituted or substituted C₁-C₈ alkyl, cycloalkylalkyl, or -TT-RR, C₁-C₈ cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O, and S; TT is an unsubstituted or substituted C₁-C₈ alkyl or C₃-C₈ cycloalkyl linker; and RR is a hydroxyl, unsubstituted or substituted C₁-C₆ alkoxy, amino, unsubstituted or substituted C₁-C₆ alkylamino, unsubstituted or substituted di-C₁-C₆ alkylamino, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀ carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; or (ii) —C(O)—R¹² or —C(O)O—R¹³, wherein R¹² is NHR^(A) or R^(A) and R¹³ is R^(A); when compounds comprise a double bond in the 6-membered ring fused to the pyrimidine ring, two R⁸ groups are present and are as defined above; when compounds do not comprise a double bond in the 6-membered ring fused to the pyrimidine ring, four R⁸ groups are present and are as defined above; or a pharmaceutically acceptable salt thereof.
 26. The method of claim 25, wherein the compound is selected from the group consisting of: Structure Reference Structure A

B

C

D

E

F

G

H

I

J

K

L

M

N

O

P

Q

R

S

T

U

V

W

X

Y

Z

AA

BB

CC

DD

EE

FF

GG

HH

II

JJ

KK

LL

MM

NN

OO

PP

QQ

RR

SS

TT

UU

VV

WW

XX

YY

ZZ

AAA

BBB

CCC

DDD

EEE

FFF

GGG

HHH

III

JJJ

KKK

LLL

MMM

NNN

OOO

PPP

QQQ

RRR

SSS

TTT

UUU

VVV

WWW

XXX


27. The method of claim 26, wherein the compound is selected from the group consisting of Compound A through Compound Z, or its pharmaceutically acceptable salt.
 28. The method of claim 26, wherein the compound is selected from the group consisting of Compound AA through ZZ, or its pharmaceutically acceptable salt.
 29. The method of claim 26, wherein the compound is selected from the group consisting of Compound AAA through XXX, or its pharmaceutically acceptable salt.
 30. The method of claim 25, wherein the autoimmune disease is arthritis.
 31. The method of claim 25, wherein the autoimmune disease is psoriasis.
 32. The method of claim 25, wherein the autoimmune disease is Crohn's disease.
 33. The method of claim 25, wherein the autoimmune disease is lupus.
 34. The method of claim 25, wherein the compound is conjugated to a targeting agent.
 35. The method of claim 34, wherein the targeting agent is an antibody or antibody fragment.
 36. The method of claim 25, wherein the compound is conjugated to a radioisotope.
 37. The method of claim 30, wherein the host is a human.
 38. The method of claim 31, wherein the host is a human.
 39. The method of claim 32, wherein the host is a human.
 40. The method of claim 1, wherein the compound is administered in combination therapy with a second active agent.
 41. The method of claim 16, wherein the compound is administered in combination therapy with a second active agent.
 42. The method of claim 25, wherein the compound is administered in combination therapy with a second active agent.
 43. A method for the treatment of abnormal T-cell proliferation that comprises administering an effective amount of a compound of Formula VI to a host in need thereof:

wherein R, R¹, R², R³, R⁴, R⁵, R⁶, R^(x), Z, m, n, and y are as defined in claim 1; each R¹⁴ is independently H, C₁-C₃ alkyl (including methyl) or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene)_(m)-C₃-C₈ cycloalkyl, -(alkylene)_(m)-aryl, -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which may be optionally independently substituted with one or more R^(x) groups as allowed by valence, and wherein two R^(x) groups bound to the same or adjacent atoms may optionally combine to form a ring; or two R¹⁴ groups bonded to the same carbon can form an exocyclic double bond; or two R¹⁴ groups bonded to the same carbon can form a carbonyl group; and when the compound of Formula VI has a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, two R¹⁴ groups are present as allowed for in Formula VI above; or when the compound of Formula VI does not include a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, four R¹⁴ groups are present as allowed for in Formula VI above; or a pharmaceutically acceptable salt thereof.
 44. The method of claim 1, wherein the compound is selected from the group consisting of:


45. The method of claim 43, wherein the compound is selected from the group consisting of:


46. A method for the treatment of abnormal T-cell proliferation that comprises administering an effective amount of a compound of Formula I, II, III, IV, or V to a host in need thereof:

wherein: Z is —(CH₂)_(x)— wherein x is 1, 2, 3 or 4 or —O—(CH₂)_(z)— wherein z is 2, 3 or 4; each X is independently CH or N; each X′ is independently CH or N; X″ is independently CH₂, S or NH, arranged such that the moiety is a stable 5-membered ring; R, R⁸, and R¹¹ are independently H, C₁-C₃ alkyl (including methyl) or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene)_(m)-C₃-C₈ cycloalkyl, -(alkylene)_(m)-aryl, -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which, other than heterocyclo, may be optionally independently substituted with one or more R^(x) groups as allowed by valence, and wherein two R^(x) groups bound to the same or adjacent atoms may optionally combine to form a ring; each R¹ is independently aryl, alkyl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally includes O or N heteroatoms in place of a carbon in the chain and two R¹'s on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle; y is 0, 1, 2, 3 or 4; R² is -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-C(O)—O-alkyl; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which, other than heterocyclo, may be optionally independently substituted with one or more R^(x) groups as allowed by valance, and wherein two R^(x) groups bound to the same or adjacent atom may optionally combine to form a ring and wherein m is 0, 1, or 2 and n is 0, 1 or 2; wherein heterocyclo may be optionally independently substituted with 1 to 3 R^(x) groups as allowed by valance, and wherein two R^(x) groups bound to the same or adjacent atom may optionally combine to form a ring; R³ and R⁴ at each occurrence are independently: (i) hydrogen or (ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which, other than heterocyclo, may be optionally independently substituted with one or more R^(x) groups as allowed by valance, and wherein two R^(x) groups bound to the same or adjacent atom may optionally combine to form a ring; or R³ and R⁴ together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R^(x) groups as allowed by valance, and wherein two R^(x) groups bound to the same or adjacent atom may optionally combine to form a ring; R⁵ and R⁵* at each occurrence is: (i) hydrogen or (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which, other than heterocyclo, may be optionally independently substituted with one or more R^(x) groups as allowed by valance; R^(x) at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene)_(m)-OR⁵, -(alkylene)_(m)-O-alkylene-OR⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-CN, -(alkylene)_(m)-C(O)—R⁵, -(alkylene)_(m)-C(S)—R⁵, -(alkylene)_(m)-C(O)—OR⁵, -(alkylene)_(m)-O—C(O)—R⁵, -(alkylene)_(m)-C(S)—OR⁵, -(alkylene)_(m)-C(O)-(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(S)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(S)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—R⁵, -(alkylene)_(m)-N(R³)—C(S)—R⁵, -(alkylene)_(m)-O—C(O)—NR³R⁴, -(alkylene)_(m)-O—C(S)—NR³R⁴, -(alkylene)_(m)-SO₂—NR³R⁴, -(alkylene)_(m)-N(R³)—SO₂—R⁵, -(alkylene)_(m)-N(R³)—SO₂—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—OR⁵, -(alkylene)_(m)-N(R³)—C(S)—OR⁵, or -(alkylene)_(m)-N(R³)—SO₂—R⁵; wherein: said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups, any of which, other than heterocyclo, may be further independently substituted with one or more -(alkylene)_(m)-CN, -(alkylene)_(m)-OR⁵*, -(alkylene)_(m)-S(O)_(n)—R⁵*, -(alkylene)_(m)-NR³*R⁴*, -(alkylene)_(m)-C(O)—R⁵*, -(alkylene)_(m)-C(═S)R⁵*, -(alkylene)_(m)-C(═O)OR⁵*, -(alkylene)_(m)-OC(═O)R⁵*, -(alkylene)_(m)-C(S)—OR⁵*, -(alkylene)_(m)-C(O)—NR³*R⁴*, -(alkylene)_(m)-C(S)—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(O)—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(S)—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(O)—R⁵*, -(alkylene)_(m)-N(R³*)—C(S)—R⁵*, -(alkylene)_(m)-O—C(O)—NR³*R⁴*, -(alkylene)_(m)-O—C(S)—NR³*R⁴*, -(alkylene)_(m)-SO₂—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—SO₂—R⁵*, -(alkylene)_(m)-N(R³*)—SO₂—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(O)—OR⁵*, -(alkylene)_(m)-N(R³*)—C(S)—OR⁵*, or -(alkylene)_(m)-N(R³*)—SO₂—R⁵*, and wherein heterocycle may be further independently substituted with one to three substitutions selected from -(alkylene)_(m)-CN, -(alkylene)_(m)-OR⁵*, -(alkylene)_(m)-S(O)_(n)—R⁵*, -(alkylene)_(m)-NR³*R⁴*, -(alkylene)_(m)-C(O)—R⁵*, -(alkylene)_(m)-C(═S)R⁵*, -(alkylene)_(m)-C(═O)OR⁵*, -(alkylene)_(m)-OC(═O)R⁵*, -(alkylene)_(m)-C(S)—OR⁵*, -(alkylene)_(m)-C(O)—NR³*R⁴*, -(alkylene)_(m)-C(S)—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(O)—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(S)—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(O)—R⁵*, -(alkylene)_(m)-N(R³*)—C(S)—R⁵*, -(alkylene)_(m)-O—C(O)—NR³*R⁴*, -(alkylene)_(m)-O—C(S)—NR³*R⁴*, -(alkylene)_(m)-SO₂—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—SO₂—R⁵*, -(alkylene)_(m)-N(R³*)—SO₂—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(O)—OR⁵*, -(alkylene)_(m)-N(R³*)—C(S)—OR⁵*, or -(alkylene)_(m)-N(R³*)—SO₂—R⁵*; n is 0, 1 or 2, and m is 0, 1; or 2 and R³* and R⁴* at each occurrence are independently: (i) hydrogen or (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which, other than heterocyclo, may be optionally independently substituted with one or more R^(x) groups as allowed by valance; or R³* and R⁴* together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R^(x) groups as allowed by valance; R⁶ is H, absent, or lower alkyl, -(alkylene)m-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which, other than heterocyclo, may be optionally independently substituted with one or more R^(x) groups as allowed by valence, and wherein two R^(x) groups bound to the same or adjacent atoms may optionally combine to form a ring; and R¹⁰ is (i) NHR^(A), wherein R^(A) is unsubstituted or substituted C₁-C₈ alkyl, cycloalkylalkyl, or -TT-RR, C₁-C₈ cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O, and S; TT is an unsubstituted or substituted C₁-C₈ alkyl or C₃-C₈ cycloalkyl linker; and RR is a hydroxyl, unsubstituted or substituted C₁-C₆ alkoxy, amino, unsubstituted or substituted C₁-C₆ alkylamino, unsubstituted or substituted di-C₁-C₆ alkylamino, unsubstituted or substituted C₆-C₁₀ aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C₃-C₁₀ carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; or (ii) —C(O)—R¹² or —C(O)O—R¹³, wherein R¹² is NHR^(A) or R^(A) and R¹³ is R^(A); when the compound of Formula I, II, III, IV, or V has a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, two R⁸ groups are present as allowed for in Formula I, II, III, IV, or V above; or when the compound of Formula I, II, III, IV, or V does not include a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, four R⁸ groups are present as allowed for in Formula I, II, III, IV, or V above; wherein each heteroaryl is an aryl ring system that contains one or more heteroatoms selected from the group O, N and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized; wherein each aryl is a carbocyclic aromatic system containing one or two rings, wherein such rings may be attached together in a fused manner, and wherein each aryl may have 1 or more R^(x) substituents; wherein each heterocyclo is a saturated or partially saturated heteroatom-containing ring radical, where the heteroatoms may be selected from nitrogen, sulfur and oxygen, wherein each heterocyclo is a monocyclic 6-8 membered ring or a 5-16 membered bicyclic ring system, and wherein each heterocyclo may have 1 to 3 R^(x) substituents; or a pharmaceutically acceptable salt thereof.
 47. A method for the treatment of abnormal T-cell proliferation that comprises administering an effective amount of a compound of Formula VI to a host in need thereof:

wherein R, R¹, R², R³, R⁴, R⁵, R⁶, R^(x), Z, m, n, and y are as defined in claim 46; each R¹⁴ is independently H, C₁-C₃ alkyl (including methyl) or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene)_(m)-C₃-C₈ cycloalkyl, -(alkylene)_(m)-aryl, -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-heteroaryl, -(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-O—R⁵, -(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any of which, other than heterocyclo, may be optionally independently substituted with one or more R^(x) groups as allowed by valence, and wherein two R^(x) groups bound to the same or adjacent atoms may optionally combine to form a ring; or two R¹⁴ groups bonded to the same carbon can form an exocyclic double bond; or two R¹⁴ groups bonded to the same carbon can form a carbonyl group; and when the compound of Formula VI has a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, two R¹⁴ groups are present as allowed for in Formula VI above; or when the compound of Formula VI does not include a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, four R¹⁴ groups are present as allowed for in Formula VI above; wherein each heteroaryl is an aryl ring system that contains one or more heteroatoms selected from the group O, N and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized; wherein each aryl is a carbocyclic aromatic system containing one or two rings, wherein such rings may be attached together in a fused manner, and wherein each aryl may have 1 or more R^(x) substituents; wherein each heterocyclo is a saturated or partially saturated heteroatom-containing ring radical, where the heteroatoms may be selected from nitrogen, sulfur and oxygen, wherein each heterocyclo is a monocyclic 6-8 membered ring or a 5-16 membered bicyclic ring system, and wherein each heterocyclo may have 1 to 3 R^(x) substituents; or a pharmaceutically acceptable salt thereof. 